U.S. patent number 5,104,888 [Application Number 07/560,466] was granted by the patent office on 1992-04-14 for thiazolidine derivatives, their preparation and use.
This patent grant is currently assigned to Sankyo Company, Limited. Invention is credited to Takashi Fujita, Kazuo Hasegawa, Eiichi Kitazawa, Yomoyuki Kurumada, Mitsuo Yamazaki, Takao Yoshioka.
United States Patent |
5,104,888 |
Yoshioka , et al. |
* April 14, 1992 |
Thiazolidine derivatives, their preparation and use
Abstract
Compounds of formula (I): ##STR1## (in which R.sup.1 -R.sup.7
are hydrogen or various organic groups, n is 1-10, Ar is an
aromatic group, U is CH.sub.2 or a carbon atom doubly bonded to
either one of its adjacent carbons, and W is >CH.sub.2,
>C.dbd.O, >CHOH, >C.dbd.NOH or various derivatives
thereof) have the ability to lower the levels of blood lipid
peroxides and blood sugars and to inhibit the activity of aldose
reductase; they may be used therapeutically for these purposes.
Inventors: |
Yoshioka; Takao (Hiromachi,
JP), Kitazawa; Eiichi (Hiromachi, JP),
Kurumada; Yomoyuki (Hiromachi, JP), Yamazaki;
Mitsuo (Hiromachi, JP), Hasegawa; Kazuo
(Hiromachi, JP), Fujita; Takashi (Hiromachi,
JP) |
Assignee: |
Sankyo Company, Limited (Tokyo,
JP)
|
[*] Notice: |
The portion of the term of this patent
subsequent to February 25, 2003 has been disclaimed. |
Family
ID: |
26374301 |
Appl.
No.: |
07/560,466 |
Filed: |
July 25, 1990 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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426533 |
Oct 24, 1989 |
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311445 |
Feb 19, 1989 |
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233984 |
Aug 11, 1988 |
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833867 |
Feb 25, 1986 |
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Foreign Application Priority Data
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Feb 26, 1985 [JP] |
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60-35324 |
Feb 26, 1985 [JP] |
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60-35325 |
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Current U.S.
Class: |
514/369; 548/183;
546/269.7; 546/256; 546/270.7; 546/283.1; 546/282.7; 514/337 |
Current CPC
Class: |
C07D
405/12 (20130101); C07D 417/14 (20130101); C07D
311/22 (20130101); C07D 311/70 (20130101); C07D
311/72 (20130101); C07D 311/24 (20130101); C07D
417/12 (20130101); C07D 495/10 (20130101) |
Current International
Class: |
C07D
495/00 (20060101); C07D 495/10 (20060101); C07D
405/12 (20060101); C07D 405/00 (20060101); C07D
417/00 (20060101); C07D 311/72 (20060101); C07D
311/24 (20060101); C07D 311/22 (20060101); C07D
311/00 (20060101); C07D 417/12 (20060101); C07D
311/70 (20060101); C07D 417/14 (20060101); C07D
417/12 (); A61K 031/425 () |
Field of
Search: |
;548/183 ;514/369,337
;546/269 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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8432559 |
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Mar 1985 |
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AU |
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61-36284 |
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Feb 1986 |
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JP |
|
Primary Examiner: Gerstl; Robert
Attorney, Agent or Firm: Frishauf, Holtz, Goodman &
Woodward
Parent Case Text
This application is a Continuation, of application Ser. No.
07/426,533, filed Oct. 24, 1989 now abandoned, which is a
continuation of Ser. No. 07/311,445 filed Feb. 15, 1989
(abandoned); which is a continuation of Ser. No. 07/233,984 filed
Aug. 11, 1988 (abandoned); which is a continuation of Ser. No.
06/833,867 filed Feb. 25, 1986 (abandoned).
Claims
We claim:
1. A compound of formula (I): ##STR619## in which: R.sup.1
represents a hydrogen atom, a C.sub.1 -C.sub.10 alkyl group or a
C.sub.7 -C.sub.13 aralkyl group;
R.sup.2 represents a hydrogen atom or a C.sub.1 -C.sub.5 alkyl
group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.23 alkanoyl
group, a C.sub.3 -C.sub.23 alkenoyl group, a C.sub.3 -C.sub.23
alkynoyl group, a substituted C.sub.1 -C.sub.23 alkanoyl, C.sub.3
-C.sub.23 alkenoyl or C.sub.3 -C.sub.23 alkynoyl group having at
least one substituent selected from the group
consisting of substituents (a), an aromatic acyl group selected
from the group consisting of benzoyl and naphthoyl, a 5 to
8-membered heterocyclic acyl group having 1 to 3 hetero atoms of N,
S or O, a group of formula --SO.sub.3 R.sup.8 where
R.sup.6 represents a hydrogen atom, an aralkyl group where the
alkyl part is C.sub.1 -C.sub.3 alkyl, a C.sub.1 -C.sub.5 alkyl
group or a C.sub.1 -C.sub.5 alkyl group having at least one
substituent selected from the group consisting of hydroxy groups
and C.sub.1 -C.sub.5 alkoxy groups,
a C.sub.1 -C.sub.10 alkyl group or a substituted C.sub.1 -C.sub.10
alkyl group having at least one substituent selected from the group
consisting of substituents (b);
R.sup.4 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkyl group
or a C.sub.1 -C.sub.5 alkoxy group;
R.sup.5 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or a C.sub.1 -C.sub.5 alkoxy group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.10 alkyl groups and
substituted C.sub.1 -C.sub.10 alkyl groups having at least one
substituent selected from the group consisting of substituents
(b);
Ar is a divalent group selected from the group consisting of
divalent carbocyclic aromatic groups, and divalent heterocyclic
aromatic groups formed from a pyridine, furan, thiophene or pyrrole
ring;
W represents a --CH.sub.2 -- group, a >C.dbd.O group, a group of
formula >CH--OR.sup.11
wherein R.sup.11 represents a hydrogen atom, a C.sub.1 -C.sub.23
alkanoyl group, a C.sub.3 -C.sub.23 alkenoyl group, a C.sub.3
-C.sub.23 alkynoyl group, a substituted C.sub.1 -C.sub.23 alkanoyl,
C.sub.3 -C.sub.23 alkenoyl or C.sub.3 -C.sub.23 alkynoyl group
having at least one substituent selected from the group consisting
of substituents (a), an aromatic acyl group selected from the group
consisting of benzoyl and napthoyl, a 5-8 membered heterocyclia
acyl having 1 to 3 heteroatoms of N, S, or O, A C.sub.1 -C.sub.10
alkyl group or a substituted C.sub.1 -C.sub.10 alkyl group having
at least one substituent selected from the group consisting of
substituents (b), or a group of formula
>C.dbd.N--O--R.sup.12
in which R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.10
alkyl group, a C.sub.1 -C.sub.10 alkyl group having at least one
substituent selected from the group consisting of substituents (b),
a C.sub.1 -C.sub.23 alkanoyl group, a C.sub.3 -C.sub.23 alkenoyl
group, a C.sub.3 -C.sub.23 alkynoyl group, a substituted C.sub.1
-C.sub.23 alkanoyl, C.sub.3 -C.sub.23 alkenoyl or C.sub.3 -C.sub.23
alkynoyl group having at least one substituent selected from the
group consisting of substituents (a), an aromatic acyl group
selected from the group consisting of benzoyl and naphthoyl or a
heterocyclic acyl group having 1 to 3 heteroatoms of N, S or O;
U represents a --CH.sub.2 -- group; or
W and U together represent a group of formula --CH.dbd.CH--; or
when W represents a carbonyl group or said group of formula
>C.dbd.N--OR.sup.12, U, R.sup.1 and the carbon atom to which
R.sup.1 is attached together represent a group of formula
--CH.dbd.C<;
n is an integer of from 1 to 3;
said aryl groups and the aryl parts of said aralkyl,
aralkyloxycarbonyl, and aromatic acyloxy being C.sub.6 -C.sub.10
carbocyclic aryl groups which are unsubstituted or have at least
one substituent selected from the group consisting of substituents
(c);
said heterocyclic groups, heterocyclic parts of said heterocyclic
acyl and acyloxy groups have from 5 to 10 ring atoms, of which from
1 to 5 are hetero-atoms selected from the group consisting of
nitrogen, oxygen and sulfur hetero-atoms, said heterocyclic groups
being unsubstituted or having at least one substituent selected
from the group consisting of substituents (d); said substituents
(a) being selected from the group consisting of aryl groups,
carboxy groups, C.sub.2 -C.sub.6 alkoxycarbonyl groups and
aralkyloxycarbonyl groups;
said substituents (b) being selected from the group consisting of
hydroxy groups, C.sub.1 -C.sub.5 alkoxy groups, aryl groups,
C.sub.1 -C.sub.23 alkanoyloxy groups, C.sub.3 -C.sub.23 alkenoyloxy
groups, C.sub.3 -C.sub.23 alkynoyloxy groups, substituted C.sub.1
-C.sub.23 alkanoyloxy, C.sub.3 -C.sub.23 alkenoyloxy or C.sub.3
-C.sub.23 alkynoyloxy groups having at least one substituent
selected from the group consisting of substituents (a), aromatic
acyloxy groups, heterocyclic acyloxy groups, groups of formula
--COOR.sup.8 where R.sup.8 is as defined above and groups of
formula --CONR.sup.9 R.sup.10 where
R.sup.9 and R.sup.10 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.5 alkyl groups or
R.sup.9 and R.sup.10, together with the nitrogen atom to which they
are attached, represent a heterocyclic group having from 5 to 7
ring atoms of which from 1 to 3 atoms, including nitrogen atom, are
hetero-atoms selected from the group consisting of nitrogen, oxygen
and sulfur hetero-atoms, said heterocyclic group being
unsubstituted, or, where said ring atoms include an additional
nitrogen hetero-atom, said additional nitrogen atom being
unsubstituted or having a single substituent selected from the
group consisting of substituents (e);
said substituents (c) being selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups,
C.sub.1 -C.sub.5 alkyl groups having at least one halogen
substituent, halogen atoms, amino groups, C.sub.1 -C.sub.5
alkylamino groups, dialkylamino groups in which each alkyl part is
C.sub.1 -C.sub.5, nitro groups, cyano groups, groups of formula
--CONR.sub.2 where R represents a C.sub.1 -C.sub.5 alkyl group or
an aryl group and hydroxy groups; and
said substituents (d) being selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups and
doubly bonded oxygen atoms;
said substituents (e) being selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkanoyl groups,
C.sub.3 -C.sub.5 alkenoyl groups and C.sub.3 -C.sub.5 alkynoyl
groups; provided that:
(.alpha.) where: R.sup.3 represents said hydrogen atom, an
unsubstituted C.sub.1 -C.sub.6 alkanoyl group, an unsubstituted
C.sub.3 -C.sub.6 alkenoyl group, an unsubstituted C.sub.3 -C.sub.6
alkynoyl group, said aromatic acyl group, said heterocyclic acyl
group, an aralkanoyl group or an aralkenoyl group; and R.sup.6 and
R.sup.7 both represent hydrogen atoms; and Ar represents a
p-phenylene group; and W represents a group of formula
>CH.sub.2, >C.dbd.O or >CH--OR.sup.11x (wherein R.sup.11x
represents a hydrogen atom, an unsubstituted C.sub.1 -C.sub.6
alkanoyl group, an unsubstituted C.sub.3 -C.sub.6 alkenoyl group,
an unsubstituted C.sub.3 -C.sub.6 alkynoyl group, said aromatic
acyl group, said heterocyclic acyl group, an aralkanoyl group or an
aralkenoyl group); and U represents said group of formula
>CH.sub.2, then
(i) when R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group, R.sup.4 represents a C.sub.6 -C.sub.10 alkyl group,
and
(ii) when R.sup.4 represents a hydrogen atom, a C.sub.1 -C.sub.5
alkyl group or a C.sub.1 -C.sub.5 alkoxy group, R.sup.1 represents
a C.sub.6 -C.sub.10 alkyl group or said C.sub.7 -C.sub.13 aralkyl
group;
(.beta.) where: R.sup.1 and R.sup.2 are independently selected from
the group consisting of hydrogen atoms and C.sub.1 -C.sub.5 alkyl
groups; and R.sup.4 and R.sup.5 are independently selected from the
group consisting of hydrogen atoms, C.sub.1 -C.sub.5 alkyl groups
and C.sub.1 -C.sub.5 alkoxy groups; and Ar represents a p-phenylene
group; and W is a group of formula >CH.sub.2, >C.dbd.O or
>CH--OR.sup.11x (where R.sup.11x is as defined above); and U
represents said group of formula >CH.sub.2 ; and n is an integer
from 1 to 3, then
at least one of R.sup.3, R.sup.6 and R.sup.7 represents said alkyl
or substituted alkyl group;
and pharmaceutically acceptable salts thereof.
2. A compound as claimed in claim 1, in which:
R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.10 alkyl
group;
R.sup.2 represents a hydrogen atom or a C.sub.1 -C.sub.3 alkyl
group;
R.sup.3 represents a hydrogen atom, a sulfo group, a C.sub.1
-C.sub.10 alkanoyl group, a C.sub.3 -C.sub.10 alkenoyl group, a
substituted C.sub.1 -C.sub.10 alkanoyl or C.sub.3 -C.sub.10
alkenoyl group having at least one substituent selected from the
group consisting of substituents (f), an arylcarbonyl group wherein
the aryl part is a C.sub.6 -C.sub.10 carbocyclic aryl group which
is unsubstituted or has at least one substituent selected from the
group consisting of substituents (g), a group of formula R.sup.13
--(CH.sub.2).sub.m --CO--, where
R.sup.13 represents a phenyl group or a phenyl group having at
least one substituent selected from the group consisting of
substituents (g), and m is an integer from 1 to 5,
a group of formula Het--CO--, where
Het represents a heterocyclic group having 5 to 6 ring atoms, of
which from 1 to 3 are hetero-atoms selected from the group
consisting of nitrogen oxygen and sulfur hetero-atoms, said
heterocyclic group being unsubstituted or having at least one
substituent selected from the group consisting of C.sub.1 -C.sub.5
alkyl groups,
a C.sub.1 -C.sub.5 alkyl group, a C.sub.1 -C.sub.5 alkyl group
substituted by a group of formula --COOR.sup.8a, where
R.sup.8a represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or an alkoxyalkyl group were both the alkoxy part and the alkyl
part are C.sub.1 -C.sub.5,
a C.sub.2 -C.sub.5 hydroxyalkyl group, a C.sub.2 -C.sub.5 alkyl
group substituted by a group of formula --O--CO--R.sup.53,
where
R.sup.53 represents a C.sub.1 -C.sub.10 alkyl group, a phenyl
group, a phenyl group having at least one substituent selected from
the group consisting of substituents (g) or a heterocyclic group
Het, as defined above,
or a C.sub.1 -C.sub.3 alkyl group substituted by a single
substituent selected from the group consisting of substituents
(h);
said substituents (f) are selected from the group consisting of
phenyl groups, carboxy groups, C.sub.2 -C.sub.6 alkoxycarbonyl
groups and benzyloxycarbonyl groups;
said substituents (g) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, trifluoromethyl groups, C.sub.1
-C.sub.5 alkoxy groups, halogen atoms, nitro groups, amino groups,
hydroxy groups and dialkylamino groups where each alkyl part is
C.sub.1 -C.sub.5 ;
said substituents (h) are selected from the group consisting of
alkylcarbamoyl groups where the alkyl part is C.sub.1 -C.sub.4,
dialkylcarbamoyl groups where each alkyl part is C.sub.1 -C.sub.4,
1-pyrrolidinylcarbonyl groups, piperidinocarbonyl groups and
morpholinocarbonyl groups;
R.sup.4 represents a C.sub.1 -C.sub.10 alkyl group or a methoxy
group;
R.sup.5 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or a methoxy group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.5 alkyl groups,
C.sub.1 -C.sub.5 alkyl groups substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined above, C.sub.2 -C.sub.5
hydroxyalkyl groups, C.sub.1 -C.sub.5 alkyl groups substituted by a
C.sub.1 -C.sub.5 alkoxy group, C.sub.2 -C.sub.5 alkyl groups
substituted by a group of formula --O--CO--R.sup.53 where R.sup.53
is as defined above, and C.sub.1 -C.sub.3 alkyl groups having a
single substituent selected from the group consisting of
substituents (h);
Ar represents a o-phenylene, m-phenylene or p-phenylene group or a
pyridine-diyl group which is attached to the part of said compound
of formula (I) of formula --(CH.sub.2).sub.n --O-- at its
2-position and is attached to the --CH.sub.2 -thiazolidine group at
its 5- or 6-position, said phenylene and pyridine-diyl groups being
unsubstituted or having a C.sub.1 -C.sub.3 alkyl substituent;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>CH--OR.sup.11 or >C.dbd.N--OR.sup.12 where
R.sup.11 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkanoyl
group, a C.sub.3 -C.sub.10 alkenoyl group, a substituted C.sub.1
-C.sub.10 alkanoyl or C.sub.3 -C.sub.10 alkenoyl group having at
least one substituent selected from the group consisting of
substituents (f), an arylcarbonyl group wherein the aryl part is a
C.sub.6 -C.sub.10 carbocyclic aryl group which is unsubstituted or
has at least one substituent selected from the group consisting of
substituents (g), a group of formula R.sup.13 --(CH.sub.2).sub.m
--CO-- where R.sup.13 and m are as defined above or a group of
formula Het--CO-- where Het is as defined above, and
R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group, a C.sub.1 -C.sub.10 alkyl group having at least one
substituent selected from the group consisting of substituents (j),
a C.sub.1 -C.sub.10 alkanoyl group, a C.sub.3 -C.sub.10 alkenoyl
group, a substituted C.sub.1 -C.sub.10 alkanoyl or C.sub.3
-C.sub.10 alkenoyl group having at least one substituent selected
from the group consisting of substituents (f), an arylcarbonyl
group wherein the aryl part is a C.sub.6 -C.sub.10 carbocyclic aryl
group which is unsubstituted or has at least one substituent
selected from the group consisting of substituents (g), or said
group of formula R.sup.13 --CH.sub.2).sub.m --CO-- or Het--CO--;
and
said substituents (j) are selected from the group consisting of
hydroxy groups, phenyl groups, phenyl groups having at least one
substituent selected from the group consisting of substituents (g),
C.sub.2 -C.sub.11 alkanoyloxy groups, C.sub.2 -C.sub.11 alkanoyloxy
groups substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined above, C.sub.3 -C.sub.11 alkenoyloxy groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined above, phenylalkenoyloxy groups where the alkenyl part
is C.sub.2 -C.sub.10 and the phenyl part is unsubstituted or has at
least one substituent selected from the group consisting of
substituents (g), benzoyloxy groups, benzoyloxy groups having at
least one substituent selected from the group consisting of
substituents (g), groups of formula --COOR.sup.8a where R.sup.8a is
as defined above, benzyloxycarbonyl groups and groups of formula
--COR.sup.9 R.sup.10 where R.sup.9 and R.sup.10 are as defined
above;
U represents
(i) where W represents a group of formula --CH.sub.2 --,
>C.dbd.O, >CH.sub.2 OR.sup.11 or >C.dbd.N--OR.sup.12, a
group of formula --CH.sub.2 --,
(ii) with W, a group of formula --CH.dbd.CH--, or
(iii) where W represents a group of formula >C.dbd.O or
>C.dbd.N--OR.sup.14, in which R.sup.14 represents any one of the
acyl groups defined for R.sup.12, with R.sup.1 and the carbon atom
to which R.sup.1 is attached, a group of formula
--CH.dbd.C<.
3. A compound as claimed in claim 2, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are defined in
claim 2;
R.sup.6 and R.sup.7 both represent hydrogen atoms;
R.sup.3 and R.sup.11 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.10 alkanoyl groups,
C.sub.3 -C.sub.10 alkenoyl groups, C.sub.1 -C.sub.10 alkanoyl or
C.sub.3 -C.sub.10 alkenoyl groups having at least one substituent
selected from the group consisting of substituents (f) as defined
in claim 2, arylcarbonyl groups as defined in claim 2, and groups
of formulae R.sup.13 --(CH.sub.2).sub.m --CO-- and Het--CO-- where
R.sup.13, m and Het are as defined in claim 2; and
R.sup.12 represents any one of the groups or atoms defined for
R.sup.3 and R.sup.11 or a C.sub.1 -C.sub.5 alkyl group of a C.sub.1
-C.sub.3 alkyl group having at least one substituent selected from
the group consisting of substituents (f) defined in claim 2.
4. A compound as claimed in claim 2, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
claim 2;
R.sup.3, R.sup.6, R.sup.7 and R.sup.12 are independently selected
from the group consisting of hydrogen atoms, C.sub.1 -C.sub.5 alkyl
groups, C.sub.1 -C.sub.5 alkyl groups substituted by a group of
formula --COOR.sup.8a where R.sup.8a is as defined in claim 2,
C.sub.2 -C.sub.5 hydroxyalkyl groups, C.sub.1 -C.sub.5 alkyl groups
substituted by a C.sub.1 -C.sub.5 alkoxy group, C.sub.2 -C.sub.5
alkyl groups substituted by a group of formula --O--CO--R.sup.53
where R.sup.53 is as defined in claim 2 and C.sub.1 -C.sub.3 alkyl
groups substituted by a single substituent selected from the group
consisting of substituents (h) as defined in claim 2; and
R.sup.11 represents a hydrogen atom, an acetyl group or a benzoyl
group; or
R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group, a C.sub.1 -C.sub.10 alkyl group having at least one
substituent selected from the group consisting of substituents (k),
a C.sub.2 -C.sub.6 alkanoyl group, a C.sub.2 -C.sub.10 alkanoyl
group having at least one substituent selected from the group
consisting of substituents (l), a C.sub.3 -C.sub.5 alkenoyl group,
a C.sub.3 -C.sub.5 alkenoyl group having at least one substituent
selected from the group consisting of substituents (l), a benzoyl
group, a benzoyl group having at least one substituent selected
from the group consisting of substituents (m), a pyridinecarbonyl
group, a furoyl group, a thenoyl group or a pyridinecarbonyl,
furoyl or thenoyl group having at least one substituent selected
from the group consisting of C.sub.1 -C.sub.5 alkyl groups;
said substituents (k) are selected from the group consisting of
hydroxy groups, phenyl groups, phenyl groups having at least one
substituent selected from the group consisting of substituents (m),
C.sub.2 -C.sub.5 alkanoyloxy groups, C.sub.2 -C.sub.10 alkanoyloxy
or C.sub.3 -C.sub.10 alkenoyloxy groups substituted by a group of
formula --COOR.sup.8a where R.sup.8a is as defined in claim 2,
C.sub.3 -C.sub.10 alkenoyloxy groups substituted by a phenyl group
where the phenyl group is unsubstituted or has at least one
substituent selected from the group consisting of substituents (m),
benzoyloxy groups, benzoyloxy groups having at least one
substituent selected from the group consisting of substituents (m),
groups of formula --COOR.sup.8a where R.sup.8a is as defined in
claim 2 and substituents (h) as defined in claim 2;
said substituents (l) are selected from the group consisting of
phenyl groups, carboxy groups, alkoxycarbonyl groups where the
alkoxy part is C.sub.1 -C.sub.5 and benzyloxycarbonyl groups;
and
said substituents (m) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups,
halogen atoms and trifluoromethyl groups.
5. A compound as claimed in claim 1, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, ethyl, isobutyl, pentyl, hexyl,
3,3-dimethylbutyl, heptyl, 4,4-dimethylpentyl, octyl,
5,5-dimethylhexyl, nonyl and 3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkanoyl
group, a C.sub.3 -C.sub.10 alkenoyl group, a substituted C.sub.1
-C.sub.10 alkanoyl or C.sub.3 -C.sub.10 alkenoyl group having at
least one substituent selected from the group consisting of
substituents (f), a benzoyl group, a benzoyl group having at least
one substituent selected from the group consisting of substituents
(n), an aralkanoyl group of formula R.sup.15 --(CH.sub.2).sub.m
--CO--
where R.sup.15 represents a phenyl group or a phenyl group having
at least one substituent selected from the group consisting of
substituents (n), and m is an integer from 1 to 5,
a pyridinecarbonyl group, a furoyl group, a thenoyl group, a
C.sub.1 -C.sub.3 alkyl group, a C.sub.1 -C.sub.3 alkyl group
substituted by a group of formula --COOR.sup.8a where
R.sup.8a represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or an alkoxyalkyl group where both the alkoxy part and the alkyl
part are C.sub.1 -C.sub.5,
a C.sub.2 -C.sub.3 hydroxyalkyl group, a C.sub.1 -C.sub.5 alkyl
group substituted by a C.sub.1 -C.sub.5 alkoxy group, a C.sub.2
-C.sub.5 alkyl group substituted by a C.sub.2 -C.sub.4 alkanoyloxy
or a benzoyloxy group or a methyl group having a single substituent
selected from the group consisting of substituents (h);
said substituents (f) are selected from the group consisting of
phenyl groups, carboxy groups, C.sub.2 -C.sub.6 alkoxycarbonyl
groups and benzyloxycarbonyl groups;
said substituents (n) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups and
halogen atoms;
R.sup.4 represents a C.sub.1 -C.sub.10 alkyl group;
R.sup.5 represents a hydrogen atom or a C.sub.1 -C.sub.3 alkyl
group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.3 alkyl groups,
C.sub.1 -C.sub.3 alkyl groups substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined above, C.sub.2 -C.sub.3
hydroxyalkyl groups, C.sub.1 -C.sub.5 alkyl groups substituted by a
C.sub.1 -C.sub.5 alkoxy group, C.sub.2 -C.sub.5 alkyl groups
substituted by a C.sub.2 -C.sub.4 alkanoyloxy of a benzoyloxy
group, and methyl groups substituted by a single substituent
selected from the group consisting of substituents (h);
said substituents (h) are selected from the group consisting of
alkylcarbamoyl groups where the alkyl part is C.sub.1 -C.sub.4,
dialkylcarbamoyl groups where each alkyl part is C.sub.1 -C.sub.4,
1-pyrrolidinylcarbonyl groups, piperidinocarbonyl groups and
morpholinocarbonyl groups;
Ar represents a o-phenylene, m-phenylene or p-phenylene group or a
pyridine-diyl group which is attached to the part of said compound
of formula (I) of formula --(CH.sub.2).sub.n --O-- at its
2-position and is attached to the --CH.sub.2 -thiazolidine group at
its 5- or 6-position, said phenylene and pyridine-diyl groups being
unsubstituted or having a methyl substituent;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>CH--OR.sup.11 or >C.dbd.N--OR.sup.12, where:
R.sup.11 represents a hydrogen atom or any one of the acyl groups
defined above for R.sup.3 ; and
R.sup.12 represents a benzyl group, any one of the groups or atoms
defined above for R.sup.3, a pyridinecarbonyl group or a
pyridinecarbonyl group having at least one substituent selected
from the group consisting of C.sub.1 -C.sub.5 alkyl groups;
and U represents
(i) where W represents a group of formula --CH.sub.2 --,
>C.dbd.O, >CH--OR.sup.11 or >C.dbd.N--OR.sup.12 , a group
of formula --CH.sub.2 --,
(ii) with W, a group of formula --CH.dbd.CH--, or
(iii) where W represents a group of formula >C.dbd.O, with
R.sup.1 and the carbon atom to which R.sup.1 is attached, a group
of formula --CH.dbd.C<.
6. A compound as claimed in claim 5, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
claim 5;
R.sup.6 and R.sup.7 are both hydrogen atoms;
R.sup.3 and R.sup.11 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.10 alkanoyl groups,
C.sub.3 -C.sub.10 alkenoyl groups, C.sub.1 -C.sub.10 alkanoyl or
C.sub.3 -C.sub.10 alkenoyl groups having at least one substituent
selected from the group consisting of substituents (f) as defined
in claim 5, benzoyl groups, benzoyl groups having at least one
substituent selected from the group consisting of substituents (n)
as defined in claim 5, groups of formula R.sup.15
--(CH.sub.2).sub.m --CO-- where R.sup.15 and m are as defined in
claim 5, pyridinecarbonyl groups, furoyl groups and thenoyl groups;
and
R.sup.12 represents a hydrogen atom, a methyl group, a benzyl
group, a t-butoxycarbonylmethyl group or any one of the acyl groups
defined above for R.sup.3 and R.sup.11.
7. A compound as claimed in claim 5, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
claim 5;
R.sup.3, R.sup.6 R.sup.7 are independently selected from the group
consisting of C.sub.1 -C.sub.3 alkyl groups, C.sub.1 -C.sub.3 alkyl
groups substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in claim 5, C.sub.2 -C.sub.3 hydroxyalkyl
groups, C.sub.1 -C.sub.5 alkyl groups substituted by a C.sub.1
-C.sub.5 alkoxy group, C.sub.2 -C.sub.5 alkyl groups substituted by
a C.sub.2 -C.sub.4 alkanoyloxy or a benzoyloxy group, and methyl
groups having a single substituent selected from the group
consisting of substituents (h) as defined in claim 5;
R.sup.11 represents a hydrogen atom;
R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.3 alkyl group
having at least one substituent selected from the group consisting
of substituents (o), a C.sub.2 -C.sub.4 alkanoyl group, a C.sub.2
-C.sub.4 alkanoyl group substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined in claim 5, an acryloyl
group, an acryloyl group having a .beta.-substituent selected from
the group consisting of substituents (f), a benzoyl group, a
benzoyl group having at least one substituent selected from the
group consisting of substituents (q), a pyridinecarbonyl group, a
pyridinecarbonyl group having at least one substituent selected
from the group consisting of C.sub.1 -C.sub.5 alkyl groups or any
one of the groups defined above for R.sup.3, R.sup.6 and R.sup.7
;
said substituents (f) are selected from the group consisting of
phenyl groups, carboxy groups, C.sub.2 -C.sub.6 alkoxycarbonyl
groups and benzyloxycarbonyl groups; and
said substituents (o) are selected from the group consisting of
carboxy groups and alkoxycarbonyl groups where the alkoxy part is
C.sub.1 -C.sub.5 ;
said substituents (q) are selected from the group consisting of
methyl groups, ethyl groups, methoxy groups and ethoxy groups.
8. A compound as claimed in claim 1 in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a group
of formula R.sup.16 OOC(CH.sub.2).sub.m CO--
where R.sup.16 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group and m is an integer from 1 to 5,
a cis- or trans- group of formula R.sup.17 OOC.CH.dbd.CH--CO--
where R.sup.17 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group or a benzyl group,
a 2-, 3- or 4-pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or an alkoxyalkyl group where both the alkoxy part and the alkyl
part are C.sub.1 -C.sub.5 ;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.3 alkyl groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined above;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>C.dbd.N--OH, >C.dbd.N--OCH.sub.2 COOH or
>C.dbd.N--OCOR.sup.18
where R.sup.18 represents a C.sub.1 -C.sub.5 alkyl group; and
U represents a group of formula --CH.sub.2 --.
9. A compound as claimed in claim 8, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar and U are as defined in
claim 8;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, a C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a
group of formula R.sup.16 OOC(CH.sub.2).sub.m CO-- where R.sup.16
and m are as defined in claim 8, a cis or trans- group of formula
R.sup.17 OOC.CH.dbd.CH--CO-- where R.sup.17 is as defined in claim
8, or a 2-, 3- or 4-pyridinecarbonyl group;
R.sup.6 and R.sup.7 are both hydrogen atoms;
W represents a group of formula >C.dbd.NOR.sup.12 where
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in
claim 8, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group or any one of the groups defined above for
R.sup.3, R.sup.6 and R.sup.7 ; and
n is 1 or 2.
10. A compound as claimed in claim 8, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar and U are as defined in
claim 8;
R.sup.3, R.sup.6 and R.sup.7 are independently selected from the
group consisting of C.sub.1 -C.sub.3 alkyl groups substituted by a
group of formula --COOR.sup.8a where R.sup.8a is as defined in
claim 8;
W represents a group of formula >CH.sub.2, >C.dbd.O or
>C.dbd.NOR.sup.12 ;
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in
claim 8, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group or any one of the groups defined above for
R.sup.3, R.sup.6 and R.sup.7 ; and
n is 1 or 2.
11. A compound as claimed in claim 2, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkanoyl
group, a C.sub.3 -C.sub.10 alkenoyl group, a C.sub.1 -C.sub.10
alkanoyl or C.sub.3 -C.sub.10 alkenoyl group having at least one
substituent selected from the group consisting of substituents (f)
as defined in claim 2, an arylcarbonyl group as defined in claim 2,
a group of formula R.sup.13 --(CH.sub.2).sub.m --CO-- or Het--CO--
where R.sup.13, m and Het are as defined in claim 2 or a C.sub.1
-C.sub.3 alkyl group substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined in claim 2;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 represents a C.sub.1 -C.sub.3 alkyl group substituted by a
group of formula --COOR.sup.8a where R.sup.8a is as defined in
claim 2;
R.sup.7 represents a hydrogen atom or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in claim 2;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula >CH.sub.2, >C.dbd.O or
>C.dbd.NOR.sup.12, where
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in
claim 2, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl group
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in claim 2;
U represents a group of formula --CH.sub.2 --; and
n is 1 or 2.
12. A compound as claimed in claim 2, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctyl
groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a group
of formula R.sup.16 OOC(CH.sub.2).sub.m CO--
where R.sup.14 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group and m is an integer from 1 to 5,
a cis- or trans- group of formula R.sup.17 OOC.CH.dbd.CH--CO--
where R.sup.17 represents a hydrogen atom, C.sub.1 -C.sub.5 alkyl
group or a benzyl group,
a 2-, 3- or 4-pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in claim 2;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.3 alkyl groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in claim 2;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O or
>C.dbd.N--OR.sup.12, where
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in
claim 2, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group, a C.sub.1 -C.sub.5 alkyl group, a C.sub.1
-C.sub.5 alkyl group substituted by a phenyl group where the phenyl
group is unsubstituted or has at least one substituent selected
from the group consisting of substituents (n), or any one of the
groups defined above for R.sup.3, R.sup.6 and R.sup.7 ;
said substituents (n) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups and
halogen atoms; and
U represents a group of formula --CH.sub.2 --.
13. A compound as claimed in claim 2, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a group
of formula R.sup.16 OOC(CH.sub.2).sub.m CO--
where R.sup.16 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group and m is an integer from 1 to 5,
a cis- or trans- group of formula R.sup.17 OOC.CH.dbd.CH--CO--
where R.sup.17 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group of a benzyl group,
a 2-, 3- or 4-pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in claim 2;
R.sup.4 represents an alkyl group selected from the group
consisting of hexyl, heptyl, octyl, 1,1,3,3-tetramethylbutyl,
1,1-dimethylbutyl and 1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.3 alkyl groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in claim 2;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O or
>C.dbd.N--OR.sup.12 where
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in
claim 2, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group, a C.sub.1 -C.sub.5 alkyl group, a C.sub.1
-C.sub.5 alkyl group substituted by a phenyl group where the phenyl
group is unsubstituted or has at least one substituent selected
from the group consisting of substituents (n), or any one of the
groups defined above for R.sup.3, R.sup.6 and R.sup.7 ;
said substituents (n) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups and
halogen atoms; and
U represents a group of formula --CH.sub.2 --.
14. A compound as claimed in claim 2, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents C.sub.1 -C.sub.3 alkyl group substituted by a
group of formula --COOR.sup.8a, where R.sup.8a is as defined in
claim 2;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are both hydrogen atoms;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>C.dbd.N--OH, or >C.dbd.N--O--(C.sub.1 -C.sub.3
alkyl)--COOR.sup.8a where R.sup.8a is as defined in claim 2;
U represents a group of formula --CH.sub.2 --; and
n is 1 or 2.
15. A compound as claimed in claim 2, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents --CH.sub.2 --COO(C.sub.1 -C.sub.5 alkyl)
group;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are both hydrogen atoms;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>C.dbd.N--OH, or >C.dbd.N--O--(C.sub.1 -C.sub.3
alkyl)--COO(C.sub.1 -C.sub.5 alkyl);
U represents a group of formula --CH.sub.2 --; and
n is 1 or 2.
16. The compound as claimed in claim 1, which is
5-[4-(6-Hydroxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)benzyl]thiazoli
dine-2,4-dione and pharmaceutically acceptable salts thereof.
17. The compound as claimed in claim 1, which is
5-{4-[6-Hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]
benzyl}thiazolidine-2,4-dione and pharmaceutically acceptable salts
thereof.
18. The compound as claimed in claim 1, which
5-{4-[6-Acetoxy-4-(E)-acetoxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]
benzyl}thiazolidine-2,4-dione and pharmaceutically acceptable salts
thereof.
19. The compound as claimed in claim 1, which is
.alpha.-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmetho
xy)benzyl]-2,4-dioxothiazolidin-3-yl}acetic acid and
pharmaceutically acceptable salts thereof.
20. The compound as claimed in claim 1, which is
.alpha.-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-
2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetic acid and
pharmaceutically acceptable salts thereof.
21. The compound as claimed in claim 1, which is
.alpha.,.alpha.'-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethy
lchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetic
acid and pharmaceutically acceptable salts thereof.
22. A pharmaceutical composition for the treatment of hyperlipaemia
or hyperglycaemia, comprising an effective amount of an active
compound in combination with a pharmaceutically acceptable carrier
or diluent, wherein the active compound is selected from the group
consisting of compounds of formula (1): ##STR620## in which:
R.sup.1 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkyl group
or a C.sub.7 -C.sub.13 aralkyl group;
R.sup.2 represents a hydrogen atom or a C.sub.1 -C.sub.5 alkyl
group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.23 alkanoyl
group, a C.sub.3 -C.sub.23 alkenoyl group, a C.sub.3 -C.sub.23
alkynoyl group, a substituted C.sub.1 -C.sub.23 alkanoyl, C.sub.3
-C.sub.23 alkenoyl or C.sub.3 -C.sub.23 alkynoyl group having at
least one substituent selected from the group consisting of
substituents (a), an aromatic acyl group selected from the group
consisting of benzoyl and naphthoyl, a 5 to 8-membered heterocyclic
acyl group having 1 to 3 hetero atoms of N, S or O, a group of
formula --SO.sub.3 R.sup.8 where
R.sup.8 represents a hydrogen atom, an aralkyl group where the
alkyl part is C.sub.1 -C.sub.3 alkyl, a C.sub.1 -C.sub.5 alkyl
group or a C.sub.1 -C.sub.5 alkyl group having at least one
substituent selected from the group consisting of hydroxy groups
and C.sub.1 -C.sub.5 alkoxy groups,
a C.sub.1 -C.sub.10 alkyl group or a substituted C.sub.1 -C.sub.10
alkyl group having at least one substituent selected from the group
consisting of substituents (b);
R.sup.4 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkyl group
or a C.sub.1 -C.sub.5 alkoxy group;
R.sup.5 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or a C.sub.1 -C.sub.5 alkoxy group;
R.sup.6 and R.sup.7 are independently selected for the group
consisting of hydrogen atoms, C.sub.1 -C.sub.10 alkyl groups and
substituted C.sub.1 -C.sub.10 alkyl groups having at least one
substituent selected from the group consisting of substituents
(b);
Ar is a divalent group selected from the group consisting of
divalent carbocyclic aromatic groups, and divalent heterocyclic
aromatic groups formed from a pyridine, furan, thiophene or pyrrole
ring;
W represents a --CH.sub.2 -- group, a >C.dbd.O group, a group of
formula >CH--OR.sup.11
where R.sup.11 represents a hydrogen atom, a C.sub.1 -C.sub.23
alkanoyl group, a C.sub.3 -C.sub.23 alkenoyl group, a C.sub.3
-C.sub.23 alkynoyl group, a substituted C.sub.1 -C.sub.23 alkanoyl,
C.sub.3 -C.sub.23 alkenoyl or C.sub.3 -C.sub.23 alkynoyl group
having at least one substituent selected from the group consisting
of
substituents (a), an aromatic acyl group selected from the group
consisting of benzoyl and napthoyl, a 5-8 membered heterocyclia
acyl having 1 to 3 heteroatoms of N, S, or O, A C.sub.1 -C.sub.10
alkyl group or a substituted C.sub.1 -C.sub.10 alkyl group having
at least one substituent selected from the group consisting of
substituents (b), or a group of formula
>C.dbd.N--O--R.sup.12
in which R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.10
alkyl group, a C.sub.1 -C.sub.10 alkyl group having at least one
substituent selected from the group consisting of substituents (b),
a C.sub.1 -C.sub.23 alkanoyl group, a C.sub.3 -C.sub.23 alkenoyl
group, a C.sub.3 -C.sub.23 alkynoyl group, a substituted C.sub.1
-C.sub.23 alkanoyl, C.sub.3 -C.sub.23 alkenoyl or C.sub.3 -C.sub.23
alkynoyl group having at least one substituent selected from the
group consisting of substituents (a), an aromatic acyl group
selected from the group consisting of benzoyl and naphthoyl or a
heterocyclic acyl group having 1 to 3 heteroatoms of N, S or O;
U represents a --CH.sub.2 -- group; or
W and U together represent a group of formula --CH.dbd.CH--; or
when W represents a carbonyl group of said group of formula
>C.dbd.N--OR.sup.12, U, R.sup.1 and the carbon atom to which
R.sup.1 is attached together represent a group of formula
--CH.dbd.C<;
n is an integer of from 1 to 3;
said aryl groups and the aryl parts of said aralkyl,
aralkyloxycarbonyl, and aromatic acyloxy being C.sub.6 -C.sub.10
carbocyclic aryl groups which are unsubstituted or have at least
one substituent selected from the group consisting of substituents
(c);
said heterocyclic groups, heterocyclic parts of said heterocyclic
acyl and acyloxy groups have from 5 to 10 ring atoms, of which 1 to
5 are hetero-atoms selected from the group consisting of nitrogen,
oxygen and sulfur hetero-atoms, said heterocyclic groups being
unsubstituted or having at least one substituent selected from the
group consisting of substituents (d); said substituents (a) being
selected from the group consisting of aryl groups, carboxy groups,
C.sub.2 -C.sub.6 alkoxycarbonyl groups and aralkyloxycarbonyl
groups;
said substituents (b) being selected from the group consisting of
hydroxy groups, C.sub.1 -C.sub.5 alkoxy groups, aryl groups,
C.sub.1 -C.sub.23 alkanoyloxy groups, C.sub.3 -C.sub.23 alkenoyloxy
groups, C.sub.3 -C.sub.23 alkynoyloxy groups, substituted C.sub.1
-C.sub.23 alkanoyloxy, C.sub.3 -C.sub.23 alkenoyloxy or C.sub.3
-C.sub.23 alkynoyloxy groups having at least one substituent
selected from the group consisting of substituents (a), aromatic
acyloxy groups, heterocyclic acyloxy groups, groups of formula
--COOR.sup.8 where R.sup.8 is as defined above and groups of
formula --CONR.sup.9 R.sup.10 where
R.sup.9 and R.sup.10 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.5 alkyl groups or
R.sup.9 and R.sup.10, together with the nitrogen atom to which they
are attached, represent a heterocyclic group having from 5 to 7
ring atoms of which from 1 to 3 atoms, including said nitrogen
atom, are hetero-atoms selected from the group consisting of
nitrogen, oxygen and sulfur hetero-atoms, said heterocyclic group
being unsubstituted, or, where said ring atoms include an
additional nitrogen hetero-atom, said additional nitrogen atom
being unsubstituted or having a single substituent selected from
the group consisting of substituents (e);
said substituents (c) being selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups,
C.sub.1 -C.sub.5 alkyl groups having at least one halogen
substituent, halogen atoms, amino groups, C.sub.1 -C.sub.5
alkylamino groups, dialkylamino groups in which each alkyl part is
C.sub.1 -C.sub.5, nitro groups, cyano groups, groups of formula
--CONR.sub.2 where R represents a C.sub.1 -C.sub.5 alkyl group or
an aryl group and hydroxy groups; and
said substituents (d) being selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups and
doubly bonded oxygen atoms;
said substituents (e) being selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkanoyl groups,
C.sub.3 -C.sub.5 alkenoykl groups and C.sub.3 -C.sub.5 alkynoyl
groups; provided that:
(.alpha.) where: R.sup.3 represents said hydrogen atom, an
unsubstituted C.sub.1 -C.sub.6 alkanoyl group, an unsubstituted
C.sub.3 -C.sub.6 alkenoyl group, an unsubstituted C.sub.3 -C.sub.6
alkynoyl group, said aromatic acyl group, said heterocyclic acyl
group, an aralkanoyl group or an aralkenoyl group; and R.sup.6 and
R.sup.7 both represent hydrogen atoms; and Ar represents a
p-phenylene group; and W represents a group of formula
>CH.sub.2, >C.dbd.O or >CH--OR.sup.11x (wherein R.sup.11x
represents a hydrogen atom, an unsubstituted C.sub.1 -C.sub.6
alkanoyl group, an unsubstituted C.sub.3 -C.sub.6 alkenoyl group,
an unsubstituted C.sub.3 -C.sub.6 alkynoyl group, said aromatic
acyl group, said heterocyclic acyl group, an aralkanoyl group or an
aralkenoyl group); and U represents said group of formula
>CH.sub.2, then
(i) when R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group, R.sup.4 represents a C.sub.6 -C.sub.10 alkyl group,
and
(ii) when R.sup.4 represents a hydrogen atom, a C.sub.1 -C.sub.5
alkyl group or a C.sub.1 -C.sub.5 alkoxy group, R.sup.1 represents
a C.sub.6 -C.sub.10 alkyl group or said C.sub.7 -C.sub.13 aralkyl
group; or
(.beta.) where: R.sup.1 and R.sup.2 are independently selected from
the group consisting of hydrogen atoms and C.sub.1 -C.sub.5 alkyl
groups; and R.sup.4 and R.sup.5 are independently selected from the
group consisting of hydrogen atoms, C.sub.1 -C.sub.5 alkyl groups
and C.sub.1 -C.sub.5 alkoxy groups; and Ar represents a p-phenylene
group; and W is a group of formula >CH.sub.2, >C.dbd.O or
>CH--OR.sup.11x (where R.sup.11x is as defined above); and U
represents said group of formula >CH.sub.2 ; and n is an integer
from 1 to 3, then
at least one of R.sup.3, R.sup.6 and R.sup.7 represents said alkyl
or substituted alkyl group;
and pharmaceutically acceptable salts thereof.
23. A composition as claimed in claim 22, in which:
R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.10 alkyl
group;
R.sup.2 represents a hydrogen atom or a C.sub.1 -C.sub.3 alkyl
group;
R.sup.3 represents a hydrogen atom, a sulfo group, a C.sub.1
-C.sub.10 alkanoyl group, a C.sub.3 -C.sub.10 alkenoyl group, a
substituted C.sub.1 -C.sub.10 alkanoyl or C.sub.3 -C.sub.10
alkenoyl group having at least one substituent selected from the
group consisting of substituents (f), an arylcarbonyl group wherein
the aryl part is a C.sub.6 -C.sub.10 carbocyclic aryl group which
is unsubstituted or has at least one substituent selected from the
group consisting of substituents (g), a group of formula R.sup.13
--(CH.sub.2).sub.m --CO--, where
R.sup.13 represents a phenyl group or a phenyl group having at
least one substituent selected from the group consisting of
substituents (g), and m is an integer from 1 to 5,
a group of formula Het--CO--, where
Het represents a heterocyclic group having 5 to 6 ring atoms, of
which from 1 to 3 are hetero-atoms selected from the group
consisting of nitrogen, oxygen and sulfur hetero-atoms, said
heterocyclic group being unsubstituted or having at least one
substituent selected from the group consisting of C.sub.1 -C.sub.5
alkyl groups,
a C.sub.1 -C.sub.5 alkyl group, a C.sub.1 -C.sub.5 alkyl group
substituted by a group of formula --COOR.sup.8a, where
R.sup.8a represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or an alkoxyalkyl group where both the alkoxy part and the alkyl
part are C.sub.1 -C.sub.5,
a C.sub.2 -C.sub.5 hydroxyalkyl group, a C.sub.2 -C.sub.5 alkyl
group substituted by a group of formula --O--CO--R.sup.53,
where
R.sup.53 represents a C.sub.1 -C.sub.10 alkyl group, a phenyl
group, a phenyl group having at least one substituent selected from
the group consisting of substituents (g) or a heterocyclic group
Het, as defined above,
or a C.sub.1 -C.sub.3 alkyl group substituted by a single
substituent selected from the group consisting of substituents
(h);
said substituents (f) are selected from the group consisting of
phenyl groups, carboxy groups, C.sub.2 -C.sub.6 alkoxycarbonyl
groups and benzyloxycarbonyl groups;
said substituents (g) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, trifluoromethyl groups, C.sub.1
-C.sub.5 alkoxy groups, halogen atoms, nitro groups, amino groups,
hydroxy groups and dialkylamino groups where each alkyl part is
C.sub.1 -C.sub.5 ;
said substituents (h) are selected from the group consisting of
alkylcarbamoyl groups where the alkyl part is C.sub.1 -C.sub.4,
dialkylcarbamoyl groups where each alkyl part is C.sub.1 -C.sub.4,
1-pyrrolidinylcarbonyl groups, piperidinocarbonyl groups and
morpholinocarbonyl groups;
R.sup.4 represents a C.sub.1 -C.sub.10 alkyl group or a methoxy
group;
R.sup.5 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or a methoxy group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.5 alkyl groups,
C.sub.1 -C.sub.5 alkyl groups substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined above, C.sub.2 -C.sub.5
hydroxyalkyl groups, C.sub.1 -C.sub.5 alkyl groups substituted by a
C.sub.1 -C.sub.5 alkoxy group, C.sub.2 -C.sub.5 alkyl groups
substituted by a group of formula --O--CO--R.sup.53 where R.sup.53
is as defined above, and C.sub.1 -C.sub.3 alkyl groups having a
single substituent selected from the group consisting of
substituents (h);
Ar represents a o-phenylene, m-phenylene or p-phenylene group or a
pyridine-diyl group which is attached to the part of said compound
of formula (I) of formula --(CH.sub.2).sub.n --O-- at its
2-position and is attached to the --CH.sub.2 -thiazolidine group at
its 5- or 6-position, said phenylene and pyridine-diyl groups being
unsubstituted or having a C.sub.1 -C.sub.3 alkyl substituent;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>CH--OR.sup.11 or >C.dbd.N--OR.sup.12 where
R.sup.11 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkanoyl
group, a C.sub.3 -C.sub.10 alkenoyl group, a substituted C.sub.1
-C.sub.10 alkanoyl or C.sub.3 -C.sub.10 alkenoyl group having at
least one substituent selected from the group consisting of
substituents (f), an arylcarbonyl group wherein the aryl part is a
C.sub.6 -C.sub.10 carbocyclic aryl group which is unsubstituted or
has at least one substituent selected from the group consisting of
substituents (g), a group of formula R.sup.13 --(CH.sub.2).sub.m
--CO-- where R.sup.13 and m are as defined above or a group of
formula Het--CO-- where Het is as defined above, and
R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group, a C.sub.1 -C.sub.10 alkyl group having at least one
substituent selected from the group consisting of substituents (j),
a C.sub.1 -C.sub.10 alkanoyl group, a C.sub.3 -C.sub.10 alkenoyl
group, a substituted C.sub.1 -C.sub.10 alkanoyl or C.sub.3
-C.sub.10 alkenoyl group having at least one substituent selected
from the group consisting of substituents (f), an arylcarbonyl
group wherein the aryl part is a C.sub.6 -C.sub.10 carbocyclic aryl
group which is unsubstituted or has at least one substituent
selected from the group consisting of substituents (g), or said
group of formula R.sup.13 --(CH.sub.2).sub.m --CO-- or Het--CO--;
and
said substituents (j) are selected from the group consisting of
hydroxy groups, phenyl groups, phenyl groups having at least one
substituent selected from the group consisting of substituents (g),
C.sub.2 -C.sub.11 alkanoyloxy groups, C.sub.2 -C.sub.11 alkanoyloxy
groups substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined above, C.sub.3 -C.sub.11 alkenoyloxy groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined above, phenylalkenoyloxy groups where the alkenyl part
is C.sub.2 -C.sub.10 and the phenyl part is unsubstituted or has at
least one substituent selected from the group consisting of
substituents (g), benzoyloxy groups, benzoyloxy groups having at
least one substituent selected from the group consisting of
substituents (g), groups of formula --COOR.sup.8a where R.sup.8a is
as defined above, benzyloxycarbonyl groups and groups of formula
--COR.sup.9 R.sup.10 where R.sup.9 and R.sup.10 are as defined
above;
U represents
(i) where W represents a group of formula --CH.sub.2 --,
>C.dbd.O, >CH.sub.2 OR.sup.11 or >C.dbd.N--OR.sup.12, a
group of formula --CH.sub.2 --,
(ii) with W, a group of formula --CH.dbd.CH--, or
(iii) where W represents a group of formula >C.dbd.O or
>C.dbd.N--OR.sup.14, in which R.sup.14 represents any one of the
acyl groups defined for R.sup.12, with R.sup.1 and the carbon atom
to which R.sup.1 is attached, a group of formula
--CH.dbd.C<.
24. A composition as claimed in claim 23, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
claim 23;
R.sup.6 and R.sup.7 both represent hydrogen atoms;
R.sup.3 and R.sup.11 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.10 alkanoyl groups,
C.sub.3 -C.sub.10 alkenoyl groups, C.sub.1 -C.sub.10 alkanoyl or
C.sub.3 -C.sub.10 alkenoyl groups having at least one substituent
selected from the group consisting of substituents (f) as defined
in claim 23, arylcarbonyl groups as defined in claim 23, and groups
of formulae R.sup.13 --(CH.sub.2).sub.m --CO-- and Het--CO-- where
R.sup.13, m and Het are as defined in claim 23; and
R.sup.12 represents any one of the groups or atoms defined for
R.sup.3 and R.sup.11 or a C.sub.1 -C.sub.5 alkyl group or a C.sub.1
-C.sub.3 alkyl group having at least one substituent selected from
the group consisting of substituents (f) defined in claim 23.
25. A composition as claimed in claim 23, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
claim 23;
R.sup.3, R.sup.6, R.sup.7 and R.sup.12 are independently selected
from the group consisting of hydrogen atom, C.sub.1 -C.sub.5 alkyl
groups, C.sub.1 -C.sub.5 alkyl groups substituted by a group of
formula --COOR.sup.8a where R.sup.8a is as defined in claim 23,
C.sub.2 -C.sub.5 hydroxyalkyl groups, C.sub.1 -C.sub.5 alkyl groups
substituted by a C.sub.1 -C.sub.5 alkoxy group, C.sub.2 -C.sub.5
alkyl groups substituted by a group of formula --O--CO--R.sup.53
where R.sup.53 is as defined in claim 23 and C.sub.1 -C.sub.3 alkyl
groups substituted by a single substituent selected from the group
consisting of substituents (h) as defined in claim 23; and
R.sup.11 represents a hydrogen atom, an acetyl group or a benzoyl
group;
R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group, a C.sub.1 -C.sub.10 alkly group having at least one
substituent selected from the group consisting of substituents (k),
a C.sub.2 -C.sub.6 alkanoyl group, a C.sub.2 -C.sub.10 alkanoyl
group having at least one substituent selected from the group
consisting of substituents (l), a C.sub.3 -C.sub.5 alkenoyl group,
a C.sub.3 -C.sub.5 alkenoyl group having at least one substituent
selected from the group consisting of substituents (l), a benzoyl
group, a benzoyl group having at least one substituent selected
from the group consisting of substituents (m), a pyridinecarbonyl
group, a furoyl group, a thenoyl group or a pyridinecarbonyl,
furoyl or thenoyl group having at least one substituent selected
from the group consisting of C.sub.1 -C.sub.5 alkyl groups;
said substituents (k) are selected from the group consisting of
hydroxy groups, phenyl groups, phenyl groups having at least one
substituent selected from the group consisting of substituents (m),
C.sub.2 -C.sub.5 alkanoyloxy groups, C.sub.2 -C.sub.10 alkanoyloxy
or C.sub.3 -C.sub.10 alkenoyloxy groups substituted by a group of
formula --COOR.sup.8a where R.sup.8a is as defined in claim 23,
C.sub.3 -C.sub.10 alkenoyloxy groups substituted by a phenyl group
where the phenyl group is unsubstituted or has at least one
substituent selected from the group consisting of substituents (m),
benzoyloxy groups, benzoyloxy groups having at least one
substituent selected from the group consisting of substituents (m),
groups of formula --COOR.sup.8a where R.sup.8a is as defined in
claim 23 and substituents (h) as defined in claim 23;
said substituents (l) are selected from the group consisting of
phenyl groups, carboxy groups, alkoxycarbonyl groups where the
alkoxy part is C.sub.1 -C.sub.5 and benzyloxycarbonyl groups; and
said substituents (m) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups,
halogen atoms and trifluoromethyl groups.
26. A composition as claimed in claim 22, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, ethyl, isobutyl, pentyl, hexyl,
3,3-dimethylbutyl, heptyl, 4,4-dimethylpentyl, octyl,
5,5-dimethylhexyl, nonyl and 3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkanoyl
group, a C.sub.3 -C.sub.10 alkenoyl group, a substituted C.sub.1
-C.sub.10 alkanoyl or C.sub.3 -C.sub.10 alkenoyl group having at
least one substituent selected from the group consisting of
substituents (f), a benzoyl group, a benzoyl group having at least
one substituent selected from the group consisting of substituents
(n), an aralkanoyl group of formula R.sup.15 --(CH.sub.2).sub.m
--CO--
where R.sup.15 represents a phenyl group or a phenyl group having
at least one substituent selected from the group consisting of
substituents (n), and m is an integer from 1 to 5,
a pyridinecarbonyl group, a furoyl group, a thenoyl group, a
C.sub.1 -C.sub.3 alkyl group, a C.sub.1 -C.sub.3 alkyl group
substituted by a group of formula --COOR.sup.8a where
R.sup.8a represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or an alkoxyalkyl group where both the alkoxy part and the alkyl
part are C.sub.1 -C.sub.5,
a C.sub.2 -C.sub.3 hydroxyalkyl group, a C.sub.1 -C.sub.5 alkyl
group substituted by a C.sub.1 -C.sub.5 alkoxy group, a C.sub.2
-C.sub.5 alkyl group substituted by a C.sub.2 -C.sub.4 alkanoyloxy
or a benzoyloxy group or a methyl group having a single substituent
selected from the group consisting of substituents (h);
said substituents (f) are selected from the group consisting of
phenyl groups, carboxy groups, C.sub.2 -C.sub.6 alkoxycarbonyl
groups and benzyloxycarbonyl groups;
said substituents (n) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups and
halogen atoms;
R.sup.4 represents a C.sub.1 -C.sub.10 alkyl group;
R.sup.5 represents a hydrogen atom or a C.sub.1 -C.sub.3 alkyl
group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.3 alkyl groups,
C.sub.1 -C.sub.3 alkyl groups substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined above, C.sub.2 -C.sub.3
hydroxyalkyl groups, C.sub.1 -C.sub.5 alkyl groups substituted by a
C.sub.1 -C.sub.5 alkoxy group, C.sub.2 -C.sub.5 alkyl groups
substituted by a C.sub.2 -C.sub.4 alkanoyloxy or a benzoyloxy
group, and methyl groups substituted by a single substituent
selected from the group consisting of substituents (h);
said substituents (h) are selected from the group consisting of
alkylcarbamoyl groups where the alkyl part is C.sub.1 -C.sub.4,
dialkylcarbamoyl groups where each alkyl part is C.sub.1 -C.sub.4,
1-pyrrolidinylcarbonyl groups, piperidinocarbonyl groups and
morpholinocarbonyl groups;
Ar represents a o-phenylene, m-phenylene or p-phenylene group or a
pyridine-diyl group which is attached to the part of said compound
of formula (I) of formula --(CH.sub.2).sub.n --O-- at its
2-position and is attached to the --CH.sub.2 -thiazolidine group at
its 5- or 6-position, said phenylene and pyridine-diyl groups being
unsubstituted or having a methyl substituent;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>CH--OR.sup.11 or >C.dbd.N--OR.sup.12, where:
R.sup.11 represents a hydrogen atom or any one of the acyl groups
defined above for R.sup.3 ; and
R.sup.12 represents a benzyl group, any one of the groups or atoms
defined above for R.sup.3, a pyridinecarbonyl group or a
pyridinecarbonyl group having at least one substituent selected
from the group consisting of C.sub.1 -C.sub.5 alkyl groups;
and U represents
(i) where W represents a group of formula --CH.sub.2 --,
>C.dbd.O, >CH--OR.sup.11 or >C.dbd.N--OR.sup.12, a group
of formula --CH.sub.2 --,
(ii) with W, a group of formula --CH.dbd.CH--, or
(iii) where W represents a group of formula >C.dbd.O, with
R.sup.1 and the carbon atom to which R.sup.1 is attached, a group
of formula --CH.dbd.C<.
27. A composition as claimed in claim 26, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
claim 26;
R.sup.6 and R.sup.7 are both hydrogen atoms;
R.sup.3 and R.sup.11 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.10 alkanoyl groups,
C.sub.3 -C.sub.10 alkenoyl groups, C.sub.1 -C.sub.10 alkanoyl or
C.sub.3 -C.sub.10 alkenoyl groups having at least one substituent
selected from the group consisting of substituents (f) as defined
in claim 26, benzoyl groups, benzoyl groups having at least one
substituent selected from the group consisting of substituents (n)
as defined in claim 26, groups of formula R.sup.15
--(CH.sub.2).sub.m --CO-- where R.sup.15 and m are as defined in
claim 26, pyridinecarbonyl groups, furoyl groups and thenoyl
groups; and
R.sup.12 represents a hydrogen atom, a methyl group, a benzyl
group, a t-butoxycarbonylmethyl group or any one of the acyl groups
defined above for R.sup.3 and R.sup.11.
28. A composition as claimed in claim 26, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
claim 26;
R.sup.3, R.sup.6 and R.sup.7 are independently selected from the
group consisting of C.sub.1 -C.sub.3 alkyl groups, C.sub.1 -C.sub.3
alkyl groups substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in claim 26, C.sub.2 -C.sub.3 hydroxyalkyl
groups, C.sub.1 -C.sub.5 alkyl groups substituted by a C.sub.1
-C.sub.5 alkoxy group, C.sub.2 -C.sub.5 alkyl groups substituted by
a C.sub.2 -C.sub.4 alkanoyloxy or a benzoyloxy group, and methyl
groups having a single substituent selected from the group
consisting of substituents (h) as defined in claim 26;
R.sup.11 represents a hydrogen atom;
R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.3 alkyl group
having at least one substituent selected from the group consisting
of substituents (o), a C.sub.2 -C.sub.4 alkanoyl group, a C.sub.2
-C.sub.4 alkanoyl group substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined in claim 26, an acryloyl
group, an acryloyl group having a .beta.-substituent selected from
the group consisting of substituents (f), a benzoyl group, a
benzoyl group having at least one substituent selected from the
group consisting of substituents (q), a pyridinecarbonyl group, a
pyridinecarbonyl group having at least one substituent selected
from the group consisting of C.sub.1 -C.sub.5 alkyl groups or any
one of the groups defined above for R.sup.3, R.sup.6 and R.sup.7
;
said substituents (f) are selected from the group consisting of
phenyl groups, carboxy groups, C.sub.2 -C.sub.6 alkoxycarbonyl
groups and benzyloxycarbonyl groups; and
said substituents (o) are selected from the group consisting of
carboxy groups and alkoxycarbonyl groups where the alkoxy part is
C.sub.1 -C.sub.5 ;
said substituents (g) are selected from the group consisting of
methyl groups, ethyl groups, methoxy groups and ethoxy groups.
29. A composition as claimed in claim 22 in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a group
of formula R.sup.16 OOC(CH.sub.2).sub.m CO--
where R.sup.16 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group and m is an integer from 1 to 5,
a cis- or trans- group of formula R.sup.17 OOC.CH.dbd.CH--CO--
where R.sup.17 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group or a benzyl group,
a 2-, 3- or 4-pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or an alkoxyalkyl group where both the alkoxy part and the alkyl
part are C.sub.1 -C.sub.5 ;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.3 alkyl groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined above;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>C.dbd.N--OH, >C.dbd.N--OCH.sub.2 COOH or
>C.dbd.N--OCOR.sup.18
where R.sup.18 represents a C.sub.1 -C.sub.5 alkyl group; and
U represents a group of formula --CH.sub.2 --.
30. A composition as claimed in claim 29, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar and U are as defined in
claim 29;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, a C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a
group of formula R.sup.16 OOC(CH.sub.2).sub.m CO-- where R.sup.16
and m are as defined in claim 29, a cis or trans- group of formula
R.sup.17 OOC.CH.dbd.CH--CO-- where R.sup.17 is as defined in claim
29, or a 2-, 3- or 4-pyridinecarbonyl group;
R.sup.6 and R.sup.7 are both hydrogen atoms;
W represents a group of formula >C.dbd.NOR.sup.12 where
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in
claim 29, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group or any one of the groups defined above for
R.sup.3, R.sup.6 and R.sup.7 ; and
n is 1 or 2.
31. A composition as claimed in claim 29, in which:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar and U are as defined in
claim 29;
R.sup.3, R.sup.6 and R.sup.7 are independently selected from the
group consisting of C.sub.1 -C.sub.3 alkyl groups substituted by a
group of formula --COOR.sup.8a where R.sup.8a is as defined in
claim 29;
W represents a group of formula >CH.sub.2, >C.dbd.O or
>C.dbd.NOR.sup.12 ;
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in
claim 29, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group or any one of the groups defined above for
R.sup.3, R.sup.6 and R.sup.7 ; and
n is 1 or 2.
32. A composition as claimed in claim 23, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkanoyl
group, a C.sub.3 -C.sub.10 alkenoyl group, a C.sub.1 -C.sub.10
alkanoyl or C.sub.3 -C.sub.10 alkenoyl group having at least one
substituent selected from the group consisting of substituents (f)
as defined in claim 23, an arylcarbonyl group as defined in claim
23, a group of formula R.sup.13 --(CH.sub.2).sub.m --CO-- of
Het--CO-- where R.sup.13, m and Het are as defined in claim 23 or a
C.sub.1 -C.sub.3 alkyl group substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined in claim 23;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 represents a C.sub.1 -C.sub.3 alkyl group substituted by a
group of formula --COOR.sup.8a where R.sup.8a is as defined in
claim 23;
R.sup.7 represents a hydrogen atom or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in claim 23;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula >CH.sub.2, >C.dbd.O or
>C.dbd.NOR.sup.12, where
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in
claim 23, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl group
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in claim 23;
U represents a group of formula --CH.sub.2 --; and
n is 1 or 2.
33. A composition as claimed in claim 23, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctyl
groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a group
of formula R.sup.16 OOC(CH.sub.2).sub.m CO--
where R.sup.16 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group and m is an integer from 1 to 5,
a cis- or trans- group of formula R.sup.17 OOC.CH.dbd.CH--CO--
where R.sup.17 represents a hydrogen atom, C.sub.1 -C.sub.5 alkyl
group of a benzyl group,
a 2-, 3- or 4-pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in claim 23;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.3 alkyl groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in claim 23;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O or
>C.dbd.N--OR.sup.12, where
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in
claim 23, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group, a C.sub.1 -C.sub.5 alkyl group, a C.sub.1
-C.sub.5 alkyl group substituted by a phenyl group where the phenyl
group is unsubstituted or has at least one substituent selected
from the group consisting of substituents (n), or any one of the
groups defined above for R.sup.3, R.sup.6 and R.sup.7 ;
said substituents (n) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups and
halogen atoms; and
U represents a group of formula --CH.sub.2 --.
34. A composition as claimed in claim 23, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a group
of formula R.sup.16 OOC(CH.sub.2).sub.m CO--
where R.sup.16 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group and m is an integer from 1 to 5,
a cis- or trans- group of formula R.sup.17 OOC.CH.dbd.CH--CO--
where R.sup.17 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group or a benzyl group,
a 2-, 3- or 4-pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in claim 23;
R.sup.4 represents an alkyl group selected from the group
consisting of hexyl, heptyl, octyl, 1,1,3,3-tetramethylbutyl,
1,1-dimethylbutyl and 1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.3 alkyl groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in claim 23;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O or
>C.dbd.N--OR.sup.12 where
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in
claim 23, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group, a C.sub.1 -C.sub.5 alkyl group, a C.sub.1
-C.sub.5 alkyl group substituted by a phenyl group where the phenyl
group is unsubstituted or has at least one substituent selected
from the group consisting of substituents (n), or any one of the
groups defined above for R.sup.3, R.sup.6 and R.sup.7 ;
said substituents (n) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups and
halogen atoms; and
U represents a group of formula --CH.sub.2 --.
35. A composition as claimed in claim 23, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents C.sub.1 -C.sub.3 alkyl group substituted by a
group of formula --COOR.sup.8a, where R.sup.8a is as defined in
claim 23;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are both hydrogen atoms;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>C.dbd.N--OH, or >C.dbd.N--O--(C.sub.1 -C.sub.3
alkyl)--COOR.sup.8a where R.sup.8a is as defined in claim 23;
U represents a group of formula --CH.sub.2 --; and
N is 1 to 2.
36. A composition as claimed in claim 23, in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents --CH.sub.2 --COO(C.sub.1 -C.sub.5 alkyl)
group;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are both hydrogen atoms;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>C.dbd.N--OH, or >C.dbd.N--O--(C.sub.1 -C.sub.3
alkyl)--COO(C.sub.1 -C.sub.5 alkyl);
U represents a group of formula --CH.sub.2 --; and
n is 1 to 2.
37. A composition as claimed in claim 22, wherein said active
compound is selected from the group consisting of:
5-[4-(6-Hydroxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)benzyl]thiazolid
ine-2,4-dione;
5-{4-[6-Hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]b
enzyl}thiazolidine-2,4-dione;
5-{4-[6-Acetoxy-4-(E)-acetoxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]b
enzyl}thiazolidine-2,4-dione;
.alpha.-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethox
y)benzyl]-2,4-dioxothiazolidin-3-yl}acetic acid;
.alpha.-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2
-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetic acid;
.alpha.,.alpha.'-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethyl
chroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetic
acid;
and pharmaceutically acceptable salts thereof.
Description
BACKGROUND TO THE INVENTION
The present invention relates to a series of novel thiazolidine
derivatives containing, on a side chain attached to the 5-position,
a chroman ring system. The invention also provides processes for
preparing these compounds and compositions and methods for using
them, especially for reducing blood lipid and blood sugar
levels.
Certain thiazolidine derivatives having the ability to lower blood
lipid and blood sugar levels are disclosed in European Patent
Publication No. 8203 and in Chem. Pharm. Bull., 30, 3580 (1982).
Certain of the thiazolidine derivatives disclosed in these
documents have the ability to lower blood lipid and blood sugar
levels, although these compounds are rather toxic.
In copending U.S. patent application Ser. No. 644,996, filed Aug.
28, 1984, the disclosure of which is incorporated herein by
reference, there are also disclosed some related thiazolidine
derivatives having a similar class of activities; some of these
prior compounds may also be used as starting materials to prepare
the compounds of the invention
We have now discovered a series of thiazolidine derivatives which
have the ability to improve the metabolism of blood lipids, that is
to say they reduce the level of blood lipid peroxides, blood
triglycerides, blood cholesterol and blood sugar, whilst having a
very low toxicity. The compounds of the invention also have the
ability to inhibit the activity of aldose reductase.
BRIEF SUMMARY OF INVENTION
The compounds of the present invention may be represented by the
formula (I): ##STR2## in which: R.sup.1 represents a hydrogen atom,
a C.sub.1 -C.sub.10 alkyl group or a C.sub.7 -C.sub.13 aralkyl
group;
R.sup.2 represents a hydrogen atom or a C.sub.1 -C.sub.5 alkyl
group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.23 alkanoyl
group, a C.sub.3 -C.sub.23 alkenoyl group, a C.sub.3 -C.sub.23
alkynoyl group, a substituted C.sub.1 -C.sub.23 alkanoyl, C.sub.3
-C.sub.23 alkenoyl or C.sub.3 -C.sub.23 alkynoyl group having at
least one substituent selected from the group consisting of
substituents (a), an aromatic acyl group, a heterocyclic acyl
group, a group of formula --SO.sub.3 R.sup.8 where
R.sup.8 represents a hydrogen atom, an aralkyl group where the
alkyl part is C.sub.1 -C.sub.3 alkyl, a C.sub.1 -C.sub.5 alkyl
group or a C.sub.1 -C.sub.5 alkyl group having at least one
substituent selected from the group consisting of hydroxy groups
and C.sub.1 -C.sub.5 alkoxy groups,
a C.sub.1 -C.sub.10 alkyl group or a substituted C.sub.1 -C.sub.10
alkyl group having at least one substituent selected from the group
consisting of substituents (b);
R.sup.4 represents a hydrogen atom, C.sub.1 -C.sub.10 alkyl group
or a C.sub.1 -C.sub.5 alkoxy group;
R.sup.5 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or a C.sub.1 -C.sub.5 alkoxy group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.10 alkyl groups and
substituted C.sub.1 -C.sub.10 alkyl groups having at least one
substituent selected from the group consisting of substituents
(b);
Ar is a divalent group selected from the group consisting of
divalent carbocyclic aromatic groups and divalent heterocyclic
aromatic groups;
W represents a --CH.sub.2 -- group, a >C.dbd.O group, a group of
formula >CH--OR.sup.11
wherein R.sup.11 represents a hydrogen atom, a C.sub.1 -C.sub.23
alkanoyl group, a C.sub.3 -C.sub.23 alkenoyl group, a C.sub.3
-C.sub.23 alkynoyl group, a substituted C.sub.1 -C.sub.23 alkanoyl,
C.sub.3 -C.sub.23 alkenoyl or C.sub.3 -C.sub.23 alkynoyl group
having at least one substituent selected from the group consisting
of substituents (a), an aromatic acyl group, a heterocyclic acyl
group, a C.sub.1 -C.sub.10 alkyl group or a substituted C.sub.1
-C.sub.10 alkyl group having at least one substituent selected from
the group consisting of substituents (b),
or a group of formula >C.dbd.N--O--R.sup.12
in which R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.10
alkyl group, a C.sub.1 -C.sub.10 alkyl group having at least one
substituent selected from the group consisting of substituents (b),
a C.sub.1 -C.sub.23 alkanoyl group, a C.sub.3 -C.sub.23 alkenoyl
group, a C.sub.3 -C.sub.23 alkynoyl group, a substituted C.sub.1
-C.sub.23 alkanoyl, C.sub.3 -C.sub.23 alkenoyl or C.sub.3 -C.sub.23
alkynoyl group having at least one substituent selected from the
group consisting of substituents (a), an aromatic acyl group or a
heterocyclic acyl group;
U represents a --CH.sub.2 -- group; or
W and U together represent a group of formula --CH.dbd.CH--; or
when W represents a carbonyl group or said group of formula
>C.dbd.N--OR.sup.12, U, R.sup.1 and the carbon atom to which
R.sup.1 is attached together represent a group of formula --CH
.dbd.C<;
n is an integer of from 1 to 3;
said aryl groups and the aryl parts of said aralkyl,
aralkyloxycarbonyl, aromatic acyl, aromatic acyloxy and divalent
aromatic groups being C.sub.6 -C.sub.10 carbocyclic aryl groups
which are unsubstituted or have at least one substituent selected
from the group consisting of substituents (c);
said heterocyclic groups, heterocyclic parts of said heterocyclic
acyl and acyloxy groups and said divalent heterocyclic aromatic
groups have from 5 to 10 ring atoms, of which from 1 to 5 are
hetero-atoms selected from the group consisting of nitrogen, oxygen
and sulfur hetero-atoms, said heterocyclic groups being
unsubstituted or having at least one substituent selected from the
group consisting of substituents (d);
said substituents (a) being selected from the group consisting of
aryl groups, carboxy groups, C.sub.2 -C.sub.6 alkoxycarbonyl groups
and aralkyloxycarbonyl groups;
said substituents (b) being selected from the group consisting of
hydroxy groups, C.sub.1 -C.sub.5 alkoxy groups, aryl groups,
C.sub.1 -C.sub.23 alkanoyloxy groups, C.sub.3 -C.sub.23 alkenoyloxy
groups, C.sub.3 -C.sub.23 alkynoyloxy groups, substituted C.sub.1
-C.sub.23 alkanoyloxy, C.sub.3 -C.sub.23 alkenoyloxy or C.sub.3
-C.sub.23 alkynoyloxy groups having at least one substitutent
selected from the group consisting of substituents (a), aromatic
acyloxy groups, heterocyclic acyloxy groups, groups of formula
--COOR.sup.8 where R.sup.8 is as defined above and groups of
formula --CONR.sup.9 R.sup.10 where
R.sup.9 and R.sup.10 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.5 alkyl groups or
R.sup.9 and R.sup.10, together with the nitrogen atom to which they
are attached, represent a heterocyclic group having from 5 to 7
ring atoms of which from 1 to 3 atoms, including said nitrogen
atom, are hetero-atoms selected from the group consisting of
nitrogen, oxygen and sulfur hetero-atoms, said heterocyclic group
being unsubstituted, or, where said ring atoms include an
additional nitrogen hetero-atom, said additional nitrogen atom
being unsubstituted or having a single substituent selected from
the group consisting of substituents (e);
said substituents (c) being selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups,
C.sub.1 -C.sub.5 alkyl groups having at least one halogen
substituent, halogen atoms, amino groups, C.sub.1 -C.sub.5
alkylamino groups, dialkylamino groups in which each alkyl part is
C.sub.1 -C.sub.5, nitro groups, cyano groups, groups of formula
--CONR.sub.2 where R represents a C.sub.1 -C.sub.5 alkyl group or
an aryl group and hydroxy groups; and
said substituents (d) being selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups and
doubly bonded oxygen atoms;
said substituents (e) being selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkanoyl groups,
C.sub.3 -C.sub.5 alkenoyl groups and C.sub.3 -C.sub.5 alkynoyl
groups; provided that:
(.alpha.) where: R.sup.3 represents said hydrogen atom, an
unsubstituted C.sub.1 -C.sub.6 alkanoyl group, an unsubstituted
C.sub.3 -C.sub.6 alkenoyl group, an unsubstituted C.sub.3 -C.sub.6
alkynoyl group, said aromatic acyl group, said heterocyclic acyl
group, an aralkanoyl group or an aralkenoyl group; and R.sup.6 and
R.sup.7 both represent hydrogen atoms; and Ar represents a
p-phenylene group; and W represents a group of formula
>CH.sub.2, >C.dbd.O or >CH--OR.sup.11x (wherein R.sup.11x
represents a hydrogen atom, an unsubstituted C.sub.1 -C.sub.6
alkanoyl group, an unsubstituted C.sub.3 -C.sub.6 alkenoyl group,
an unsubstituted C.sub.3 -C.sub.6 alkynoyl group, said aromatic
acyl group, said heterocyclic acyl group, an aralkanoyl group or an
aralkenoyl group); and U represents said group of formula
>CH.sub.2, then
(i) when R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group, R.sup.4 represents a C.sub.6 -C.sub.10 alkyl group,
and
(ii) when R.sup.4 represents a hydrogen atom, a C.sub.1 -C.sub.5
alkyl group or a C.sub.1 -C.sub.5 alkoxy group, R.sup.1 represents
a C.sub.6 -C.sub.10 alkyl group or said C.sub.7 -C.sub.13 aralkyl
group; or
(.beta.) where: R.sup.1 and R.sup.2 are independently selected from
the group consisting of hydrogen atoms and C.sub.1 -C.sub.5 alkyl
groups; and R.sup.4 and R.sup.5 are independently selected from the
group consisting of hydrogen atoms, C.sub.1 -C.sub.5 alkyl groups
and C.sub.1 -C.sub.5 alkoxy groups; and Ar represents a p-phenylene
group; and W is a group of formula >CH.sub.2, >C.dbd.O or
>CH--OR.sup.11x (where R.sup.11x is as defined above); and U
represents said group of formula >CH.sub.2 ; and n is an integer
from 1 to 3, then
at least one of R.sup.3, R.sup.6 and R.sup.7 represents said alkyl
or substituted alkyl group;
and pharmaceutically acceptable salts thereof.
The invention also provides processes for preparing the compounds
of the invention, as described in more detail hereafter.
The invention still further provides a pharmaceutical composition
comprising a compound of formula (I) or a pharmaceutically
acceptable salt thereof in admixture with a pharmaceutically
acceptable carrier or diluent.
The invention still further provides a method of reducing blood
lipid and blood sugar levels in an animal, especially a mammal,
e.g. a human being, by administering to said animal an effective
amount of a compound of formula (I) or a pharmaceutically
acceptable salt thereof.
DETAILED DESCRIPTION OF INVENTION
In the compounds of the invention, where R.sup.1, R.sup.3, R.sup.6,
R.sup.7, R.sup.11 or R.sup.12 represents a C.sub.1 -C.sub.10 alkyl
group, this may be a straight or branched chain group and examples
include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl,
1-ethylpropyl, hexyl, isohexyl, neohexyl, 1-methylpentyl,
3-methylpentyl, 1,1-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl,
1-methyl-1-ethylpropyl, heptyl, 1-methylhexyl, 1-propylbutyl,
4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-ethylhexyl,
5,5-dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl
and 7,7-dimethyloctyl groups.
Where R.sup.1 or R.sup.8 represents an aralkyl group, this may be
substituted or unsubstituted and is a C.sub.7 -C.sub.13 aralkyl
group, for example substituted or unsubstituted benzyl, phenethyl,
3-phenylpropyl or 4-phenylbutyl groups. Examples of suitable
substituents include: C.sub.1 -C.sub.4 alkyl groups, particularly
the methyl, ethyl and propyl groups; C.sub.1 -C.sub.4 alkoxy
groups, particularly the methoxy, ethoxy and propoxy groups; and
halogen atoms, such as the fluorine, chlorine, bromine and iodine
atoms.
Where R.sup.2 represents an alkyl group, this may be a C.sub.1
-C.sub.5 alkyl group, for example a methyl, ethyl, propyl,
isopropyl, butyl, isobutyl or pentyl group.
Where the acyl group represented by R.sup.3, R.sup.11 or R.sup.12
is an aliphatic acyl group, this may be a saturated or unsaturated
group (the terms "saturated" and "unsaturated" referring to the
carbon-carbon bonds) having up to 23 carbon atoms and is thus a
C.sub.1 -C.sub.23 alkanoyl, C.sub.3 -C.sub.23 alkenoyl or C.sub.3
-C.sub.23 alkynoyl group, which may be unsubstituted or may have
one or more substituents selected from substituents (a), for
example selected from the group consisting of aryl groups, carboxy
groups, C.sub.2 -C.sub.6 alkoxycarbonyl groups or
aralkyloxycarbonyl groups. Examples of such aliphatic acyl groups
include the formyl, acetyl, propionyl, propiolyl, butyryl,
isobutyryl, pivaloyl, hexanoyl, acryloyl, methacryloyl, crotonoyl,
octanoyl, decanoyl, tridecanoyl, pentadecanoyl, hexadecanoyl,
heptadecanoyl, octadecanoyl, nonadecanoyl,
2,6,10,14-tetramethylnonadecanoyl and icosanoyl groups. Such groups
may be unsubstituted or have one or more (preferably one)
substituents as defined above. Suitable aryl substituents include
the phenyl and 1- or 2-naphthyl groups, especially the phenyl
group, which may themselves be unsubstituted or have one or more
substituents selected from substituents (c), especially C.sub.1
-C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups, halogen
atoms, hydroxy groups, nitro groups, amino groups and dialkylamino
groups where each alkyl part is C.sub.1 -C.sub.5 ; specific
examples of the resulting araliphatic acyl groups are given
hereafter. Suitable alkoxycarbonyl groups (as substituents on these
acyl groups) include straight or branched chain C.sub.C.sub.2
-C.sub.6 groups (i.e. the alkoxy part is C.sub.1 -C.sub.5), such as
the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,
sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl and
isopentyloxycarbonyl groups. Suitable aralkyloxycarbonyl groups
include those where the aralkyl part is as exemplified above in
relation to R.sup.1.
Examples of the alkanoyl, alkenoyl and alkynoyl groups which may be
included in substituents (e) are those unsubstituted acyl groups
exemplified above and having up to 5 carbon atoms.
Where R.sup.3, R.sup.11 or R.sup.12 represents an aromatic acyl
group, this is preferably an arylcarbonyl group in which the aryl
part is as defined above, but is preferably a phenyl or naphthyl
(1- or 2-naphthyl) group, which may be unsubstituted or may have
one or more of the substituents (c) defined above. Examples of such
aromatic acyl groups include the benzoyl, 4-nitrobenzoyl,
3-fluorobenzoyl, 2-chlorobenzoyl, 4-aminobenzoyl,
3-dimethylaminobenzoyl, 2-methoxybenzoyl, 3,4-dichlorobenzoyl,
3,5-di-t-butyl-4-hydroxybenzoyl and 1-naphthoyl groups.
Where R.sup.3, R.sup.11 or R.sup.12 represents a heterocyclic acyl
group, this is preferably a heterocyclic-carbonyl group, in which
the heterocyclic part is as defined above, but is preferably a
heterocyclic group having from 5 to 8, and more preferably 5 or 6,
ring atoms, of which from 1 to 3, and preferably 1, are
hetero-atoms selected from the group consisting of nitrogen, oxygen
and sulfur hetero-atoms. Such heterocyclic groups may be
unsubstituted or may have at least one substituent (d), as defined
above. Examples of such heterocyclic acyl groups include the
2-furoyl, 3-thenoyl, 3-pyridinecarbonyl and 4-pyridinecarbonyl
groups.
Where R.sup.3, R.sup.11 or R.sup.12 represents an araliphatic acyl
group, this is preferably an aralkanoyl or aralkenoyl group, in
which the aryl part is as defined above, but is preferably a phenyl
or naphthyl group, more preferably a phenyl group, which may be
unsubstituted or may have one or more of the substituents (c)
defined above. The alkanoyl or alkenoyl part is preferably a
C.sub.2 -C.sub.6 alkanoyl or C.sub.3 -C.sub.6 alkenoyl group, more
preferably an acetyl, propionyl or acryloyl group. Examples of such
araliphatic acyl groups include the phenylacetyl,
.alpha.-(4-chlorophenyl)acetyl, 3-phenylpropionyl and cinnamoyl
groups.
Where R.sup.3, R.sup.6, R.sup.7, R.sup.11 or R.sup.12 represents a
substituted alkyl group, this is a C.sub.1 -C.sub.10 alkyl group
having at least one of the substituents defined above as
substituents (b). The parent alkyl group may be any one of those
exemplified above. Examples of the substituents include:
hydroxy groups;
alkanoyloxy, alkenoyloxy and alkynoyloxy groups (which may be
substituted or unsubstituted), aromatic acyloxy groups and
heterocyclic acyloxy groups, examples of which are the acyloxy
groups corresponding to the acyl groups exemplified above in
relation to R.sup.3, R.sup.11 and R.sup.12 ;
carboxy groups (i.e. --COOR.sup.8 where R.sup.8 is hydrogen);
aralkyloxycarbonyl groups (i.e. --COOR.sup.8 where R.sup.8 is
aralkyl), e.g. where the aralkyl part is as exemplified above in
relation to R.sup.1 ;
C.sub.2 -C.sub.6 alkoxycarbonyl groups (i.e. --COOR.sup.8 where
R.sup.8 is C.sub.1 -C.sub.5 alkyl) e.g. as exemplified above in
relation to substituents on aliphatic acyl groups represented by
R.sup.3, R.sup.11 and R.sup.12 ;
C.sub.2 -C.sub.6 hydroxyalkoxycarbonyl groups (i.e. --COOR.sup.8
where R.sup.8 is C.sub.1 -C.sub.5 hydroxyalkyl), e.g.
hydroxy-substituted analogs of the alkoxycarbonyl groups mentioned
above, especially 2-hydroxyethoxycarbonyl, 3-hydroxypropoxycarbonyl
and 2-hydroxypropoxycarbonyl groups;
alkoxyalkoxycarbonyl groups (i.e. --COOR.sup.8 where R.sup.8 is
C.sub.1 -C.sub.5 alkyl having a C.sub.1 -C.sub.5 alkoxy
substituent), e.g. alkoxy-substituted analogs of the alkoxycarbonyl
groups mentioned above, especially methoxymethoxycarbonyl,
ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl,
2-ethoxyethoxycarbonyl, 2-propoxyethoxycarbonyl,
1-methoxyethoxycarbonyl, 3-methoxypropoxycarbonyl,
3-ethoxypropoxycarbonyl, 3-propoxypropoxycarbonyl,
3-butoxypropoxycarbonyl, 2-methoxy-1-methylethoxycarbonyl,
2-ethoxy-1-methylethoxycarbonyl, 3-isopropoxypropoxycarbonyl,
4-methoxybutoxycarbonyl, 4-ethoxybutoxycarbonyl,
4-propoxybutoxycarbonyl, 4-butoxybutoxycarbonyl,
4-t-butoxybutoxycarbonyl, 5-methoxypentyloxycarbonyl and
5-ethoxypentyloxycarbonyl groups;
carbamoyl groups (i.e. --CONR.sup.9 R.sup.10 where R.sup.9
.dbd.R.sup.10 .dbd.H);
mono- and di- alkylcarbamoyl groups (i.e. the groups --CONR.sup.9
R.sup.10 where one or both of R.sup.9 and R.sup.10 represents a
C.sub.1 -C.sub.5 alkyl group), e.g. the methylcarbamoyl,
ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl,
butylcarbamoyl, sec-butylcarbamoyl, pentylcarbamoyl,
isopentylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl,
dipropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl,
N-methyl-N-ethylcarbamoyl, N-methyl-N-propylcarbamoyl and
N-ethyl-N-propylcarbamoyl groups; and
nitrogen-containing heterocyclic acyl groups (i.e. --CONR.sup.9
R.sup.10 where R.sup.9, R.sup.10 and the nitrogen atom together
form an optionally substituted heterocyclic group), for example the
1-pyrrolylcarbonyl, 1-imidazolylcarbonyl, 3-thiazolidinylcarbonyl,
1-pyrrolidinylcarbonyl, 1-pyrrolinylcarbonyl,
1-imidazolinylcarbonyl, 1-imidazolidinylcarbonyl,
3-methyl-1-imidazolidinylcarbonyl,
3-ethyl-1-imidazolidinylcarbonyl,
3-t-butyl-1-imidazolidinylcarbonyl,
3-acetyl-1-imidazolidinylcarbonyl,
3-butyryl-1-imidazolidinylcarbonyl,
3valeryl-1-imidazolidinylcarbonyl,
3-pivaloyl-1-imidazolidinylcarbonyl, piperidinocarbonyl,
1-piperazinylcarbonyl, 4-methyl-1-piperazinylcarbonyl,
4-ethyl-1-piperazinylcarbonyl, 4-propyl-1-piperazinylcarbonyl,
4-butyl-1-piperazinylcarbonyl, 4-pentyl-1-piperazinylcarbonyl,
4-t-butyl-1-piperazinylcarbonyl, 4-acetyl-1-piperazinylcarbonyl,
4-formyl-1-piperazinylcarbonyl, 4-propionyl-1-piperazinylcarbonyl,
4-acryloyl-1-piperazinylcarbonyl,
4-methacryloyl-1-piperazinylcarbonyl,
4-propioloyl-1-piperazinylcarbonyl,
4-butyryl-1-piperazinylcarbonyl, 4-isovaleryl-1-piperazinylcarbonyl
and morpholinocarbonyl groups.
Where R.sup.4 represents an alkyl group, this has from 1 to 10
carbon atoms and is a straight or branched chain group. Certain
examples of such alkyl groups have been given above in relation to
such groups which may be represented by R.sup.1. However, preferred
examples of alkyl groups which may be represented by R.sup.4
include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl, isopentyl, neopentyl, t-pentyl, hexyl,
1,1-dimethylbutyl, 1,3-dimethylbutyl, heptyl, 1,1-diethylpropyl,
octyl, 1-methylheptyl, 2-ethylhexyl, 1,1,3,3-tetramethylbutyl,
nonyl, decyl and 3,7-dimethyloctyl groups.
Where R.sup.4, R.sup.5 or substituent (b) represents an alkoxy
group, this may have from 1 to 5 carbon atoms and may be a straight
or branched chain group. Examples of such alkoxy groups include the
methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and
pentyloxy groups.
Where R.sup.5 or substituent (e) represents an alkyl group, this
may have from 1 to 5 carbon atoms and may be a straight or branched
chain group. Examples of such alkyl groups which may be represented
by R.sup.5 are included amongst the alkyl groups which may be
represented by R.sup.1 or by R.sup.4. However, preferred alkyl
groups which may be represented by R.sup.5 include the methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and isopentyl
groups.
Where Ar represents a divalent carbocyclic aromatic group, this may
be substituted or unsubstituted and has from 6 to 10 ring carbon
atoms. Examples of such divalent aromatic groups include the
p-phenylene, o-phenylene and m-phenylene groups. Where such a group
is substituted, it may have at least one of the substituents (c)
defined above, but preferably C.sub.1 -C.sub.5 alkyl groups (e.g.
the methyl, ethyl, propyl, isopropyl, butyl or pentyl groups) or
C.sub.1 -C.sub.5 alkoxy groups (e.g. the methoxy, ethoxy,
isopropoxy, t-butoxy or pentyloxy groups).
Where Ar represents a divalent aromatic heterocyclic group, the
heterocyclic group is preferably a pyridine, furan, thiophene or
pyrrole ring, which may be unsubstituted or have at least one of
the substituents (d) defined above, and the two free valences may
be in a variety of positions. Specific examples of such groups are
as follows, in which the first number given denotes the position of
attachment of the heterocyclic group to the group of formula
--(CH.sub.2).sub.n --O--, whilst the second number given denotes
the position of attachment of the heterocyclic group to the
--CH.sub.2 -thiazolidine group; the pyrid-2,3-diyl, pyrid-2,4-diyl,
pyrid-2,5-diyl, pyrid-2,6-diyl, pyrid-3,4-diyl, pyrid-3,5-diyl,
pyrid-3,6-diyl, pyrid-3,2-diyl, pyrid-4,3-diyl, pyrid-4,2-diyl,
furan-2,3-diyl, furan-2,4-diyl, furan-2,5-diyl, furan-3,2-diyl,
furan-4,2-diyl, thien-2,3-diyl, thien-2,4-diyl, thien-2,5-diyl,
thien-3,2-diyl, thien-4,2-diyl, pyrrol-2,3-diyl, pyrrol-2,4-diyl,
pyrrol-2,5-diyl, pyrrol-3,2-diyl or pyrrol-4,2-diyl groups. Such
groups may be unsubstituted or, if desired, may have at least one,
and preferably only one, substituted selected from those
substituents (d) defined above, but preferably C.sub.1 -C.sub.6
alkyl groups (e.g. the methyl, ethyl, isopropyl, t-butyl or pentyl
groups) or C.sub.1 -C.sub.6 alkoxy groups (e.g. the methoxy,
ethoxy, isopropoxy, t-butoxy or pentyloxy groups).
W may represent a methylene (--CH.sub.2 --) group, a carbonyl
(>C.dbd.O) group, a group of formula >CH--OR.sup.11 (in which
R.sup.11 is as defined above) or a group of formula
>C.dbd.NOR.sup.12 (where R.sup.12 is as defined above and may be
the same as or different from the atom or group represented by
R.sup.3). Examples of the acyl and alkyl groups which may be
represented by R.sup.11 and R.sup.12 are as given above. Where
R.sup.12 represents a group of formula --CONR.sup.9 R.sup.10, i.e.
a carbamoyl or mono- or di-alkylcarbamoyl group, examples of such
groups are as given in relation to the similar groups which may be
represented by substituents (b).
Alternatively, W and U may together form a double bond, e.g. as
illustrated by the compounds of formula (I-12) described
hereafter.
U preferably represents a methylene group. However, as mentioned
above, it may form a double bond with W, or, when W represents a
carbonyl group or a group of formula >C.dbd.N--OR.sup.12, U may,
together with R.sup.1 and the carbon atom to which the group
represented by R.sup.1 is attached, form a group of formula
--CH.dbd.C>, e.g. as illustrated in the compounds of formulae
(I-8) to (I-11), defined hereafter.
Where substituent (c) is a C.sub.1 -C.sub.5 alkyl group having at
least one halogen substituent, the alkyl part may be any one of
those C.sub.1 -C.sub.5 alkyl groups defined above in relation to
R.sup.5, both straight and branched chain groups. The resulting
haloalkyl group may have one or more halogen atoms (e.g. fluorine,
chlorine, bromine or iodine atoms) up to complete perhalogenation.
Examples of such groups include the chloromethyl, dichloromethyl,
iodomethyl, bromethyl, fluoromethyl, trifluoromethyl,
2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2-fluoroethyl,
1,2-dibromoethyl, 1,2-dichloroethyl, 2,2-dichloroethyl,
2,2-difluoroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl,
2,2,2-tribromoethyl, 1,2,2-trichloroethyl, 1,2,3-trichloropropyl,
4-chlorobutyl and 5-fluoropentyl groups, of which the
trifluoromethyl group is preferred.
Where the compounds of the present invention contain an acidic
group in their molecule, for example where they contain a carboxy
group or where R.sup.3 represents a hydrogen atom and the resulting
hydroxy group is of an acidic character or where R.sup.3 represents
a sulfo (--SO.sub.3 H) group, then the compounds of the invention
may form salts with cations. There is no limitation upon the nature
of such salts, provided that, where they are to be used for
therapeutic purposes, they are pharmaceutically acceptable, which,
as is well-known in the art, means that they do not have reduced
activity (or unacceptably reduced activity) or increased toxicity
(or unacceptably increased toxicity) compared with the free
compound of formula (I). Where, however, they are to be used for
non-therapeutic purposes, e.g. as intermediates in the preparation
of other compounds, even this limitation does not apply. Suitable
salts include, for example: alkali metal salts, such as the sodium
or potassium salts; alkaline earth metal salts, such as the calcium
or magnesium salts; other metal salts, such as the aluminum or iron
salts; salts with basic amino acids, such as the lysine or arginine
salts; ammonium salts; and salts with organic amines, such as the
cyclohexylammonium, diisopropylammonium and triethylammonium
salts.
The compounds of the invention may also, depending upon the
particular substituents, contain basic groups in their molecules
and, in such a case, they can also form acid addition salts. As
with the salts mentioned above, there is no particular limitation
on the nature of the acid forming such a salt, provided that, where
the compound is to be used for therapeutic purposes, the resulting
salt is pharmaceutically acceptable. Examples of suitable acids
include: inorganic acids, such as hydrochloric acid, sulfuric acid,
nitric acid or phosphoric acid; organic carboxylic acids, such as
acetic acid, tartaric acid, maleic acid, fumaric acid, malic acid,
glutamic acid or aspartic acid; and organic sulfonic acids, such as
p-toluenesulfonic acid or methanesulfonic acid.
Preferred classes of compound of the present invention are as
follows:
(1) Compounds of formula (I) in which:
R.sup.1 represents a hydrogen atom or a C.sub.1 -C.sub.10 alkyl
group;
R.sup.2 represents a hydrogen atom or a C.sub.1 -C.sub.3 alkyl
group;
R.sup.3 represents a hydrogen atom, a sulfo group, a C.sub.1
-C.sub.10 alkanoyl group, a C.sub.3 -C.sub.10 alkenoyl group, a
substituted C.sub.1 -C.sub.10 alkanoyl or C.sub.3 -C.sub.10
alkenoyl group having at least one substituent selected from the
group consisting of substituents (f), an arylcarbonyl group wherein
the aryl part is a C.sub.6 -C.sub.10 carbocyclic aryl group which
is unsubstituted or has at least one substituent selected from the
group consisting of substituents (g), a group of formula R.sup.13
--(CH.sub.2).sub.m --CO--, where
R.sup.13 represents a phenyl group or a phenyl group having at
least one substituent selected from the group consisting of
substituents (g), and m is an integer from 1 to 5,
a group of formula Het--CO--, where
Het represents a heterocyclic group having 5 or 6 ring atoms, of
which from 1 to 3, and preferably 1, are hetero-atoms selected from
the group consisting of nitrogen, oxygen and sulfur hetero-atoms,
said heterocyclic group being unsubstituted or having at least one
substituent selected from the group consisting of C.sub.1 -C.sub.5
alkyl groups,
a C.sub.1 -C.sub.5 alkyl group substituted by a group of formula
--COOR.sup.8a, where
R.sup.8a represents a hydrogen atom, C.sub.1 -C.sub.5 alkyl group
or an alkoxyalkyl group where both the alkoxy part and the alkyl
part are C.sub.1 -C.sub.5,
a C.sub.2 -C.sub.5 hydroxyalkyl group, an alkoxyalkyl group where
both the alkoxy part and the alkyl part are C.sub.1 -C.sub.5, a
C.sub.2 -C.sub.5 alkyl group substituted by a group of formula
--O--CO--R.sup.53, where
R.sup.53 represents a C.sub.1 -C.sub.10 alkyl group, a phenyl
group, a phenyl group having at least one substituent selected from
the group consisting of substituents (g) or a heterocyclic group
Het, as defined above,
or a C.sub.1 -C.sub.3 alkyl group substituted by a single
substituent selected from the group consisting of substituents
(h);
said substituents (f) are selected from the group consisting of
phenyl groups, carboxy groups, C.sub.2 -C.sub.6 alkoxycarbonyl
groups and benzyloxycarbonyl groups;
said substituents (g) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, trifluoromethyl groups, C.sub.1
-C.sub.5 alkoxy groups, halogen atoms, nitro groups, amino groups,
hydroxy groups and dialkylamino groups where each alkyl part is
C.sub.1 -C.sub.5 ;
said substituents (h) are selected from the group consisting of
alkylcarbamoyl groups where the alkyl part is C.sub.1 -C.sub.4,
dialkylcarbamoyl groups where each alkyl part is C.sub.1 -C.sub.4,
1-pyrrolidinylcarbonyl groups, piperidinocarbonyl groups and
morpholinocarbonyl groups;
R.sup.4 represents a C.sub.1 -C.sub.10 alkyl group or a methoxy
group;
R.sup.5 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl group
or a methoxy group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.5 alkyl groups,
C.sub.1 -C.sub.5 alkyl groups substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined above, C.sub.2 -C.sub.5
hydroxyalkyl groups, C.sub.1 -C.sub.5 alkyl groups substituted by a
C.sub.1 -C.sub.5 alkoxy group, C.sub.2 -C.sub.5 alkyl groups
substituted by a group of formula --O--CO--R.sup.53 where R.sup.53
is as defined above, and C.sub.1 -C.sub.3 alkyl groups having a
single substituent selected from the group consisting of
substituents (h);
Ar represents a o-phenylene, m-phenylene or p-phenylene group or a
pyridine-diyl group which is attached to the part of said compound
of formula (I) of formula --(CH.sub.2).sub.n --O-- at its
2-position and is attached to the --CH.sub.2 -thiazolidine group at
its 5- or 6-position, said phenylene and pyridine-diyl groups being
unsubstituted or having a C.sub.1 -C.sub.3 alkyl substituent;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>CH--OR.sup.11 or >C.dbd.N--OR.sup.12 where
R.sup.11 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkanoyl
group (preferably an acetyl group), a C.sub.3 -C.sub.10 alkenoyl
group, a substituted C.sub.1 -C.sub.10 alkanoyl or C.sub.3
-C.sub.10 alkenoyl group having at least one substituent selected
from the group consisting of substituents (f), an arylcarbonyl
group wherein the aryl part is a C.sub.6 -C.sub.10 carbocyclic aryl
group which is unsubstituted or has at least one substituent
selected from the group consisting of substituents (g), a group of
formula R.sup.13 --(CH.sub.2).sub.m --CO-- where R.sup.13 and m are
as defined above or a group of formula HET--CO-- where Het is as
defined above, and
R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group, a C.sub.1 -C.sub.10 alkyl group having at least one
substituent selected from the group consisting of substituents (j),
a C.sub.1 -C.sub.10 alkanoyl group, a C.sub.3 -C.sub.10 alkenoyl
group, a substituted C.sub.1 -C.sub.10 alkanoyl or C.sub.3
-C.sub.10 alkenoyl group having at least one substituent selected
from the group consisting of substituents (f), an arylcarbonyl
group wherein the aryl part is a C.sub.6 -C.sub.10 carbocyclic aryl
group which is unsubstituted or has at least one substituent
selected from the group consisting of substituents (g), or said
group of formula R.sup.13 --(CH.sub.2).sub.m --CO-- or Het--CO--;
and
said substituents (j) are selected from the group consisting of
hydroxy groups, C.sub.1 -C.sub.5 alkoxy groups, phenyl groups,
phenyl proups having at least one substituent selected form the
group consisting of substituents (g), C.sub.2 -C.sub.11 alkanoyloxy
groups, C.sub.2 -C.sub.11 alkanoyloxy groups substituted by a group
of formula --COOR.sup.8a where R.sup.8a is as defined above,
C.sub.3 -C.sub.11 alkanoyloxy groups substituted by a group of
formula --COOR.sup.8a where R.sup.8a is as defined above, C.sub.3
-C.sub.11 alkenoyloxy groups substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined above, phenylalkenoyloxy
groups where the alkenyl part is C.sub.2 -C.sub.10 and the phenyl
part is unsubstituted or has at least one substituent selected from
the group consisting of substituents (g), benzoyloxy groups,
benzoyloxy groups having at least one substituent selected from the
group consisting of substituents (g), groups of formula
--COOR.sup.8a where R.sup.8a is as defined above, benzyloxycarbonyl
groups and groups of formula --COR.sup.9 R.sup.10 where R.sup.9 and
R.sup.10 are as defined above;
U represents
(i) where W represents a group of formula --CH.sub.2 --,
>C.dbd.O, >CH.sub.2 OR.sup.11 or >C.dbd.N--OR.sup.12, a
group of formula --CH.sub.2 --,
(ii) with W, a group of formula --CH.dbd.CH--, or
(iii) where W represents a group of formula >C.dbd.O or
>C.dbd.N--OR.sup.14, in which R.sup.14 represents any one of the
acyl groups defined for R.sup.12, with R.sup.1 and the carbon atom
to which R.sup.1 is attached, a group of formula
--CH.dbd.C<.
(2) Compounds as defined in (1) above, where:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
(1);
R.sup.6 and R.sup.7 both represent hydrogen atoms;
R.sup.3 and R.sup.11 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.10 alkanoyl groups,
C.sub.3 -C.sub.10 alkenoyl groups, C.sub.1 -C.sub.10 alkanoyl or
C.sub.3 -C.sub.10 alkenoyl groups having at least one substituent
selected from the group consisting of substituents (f),
arylcarbonyl groups as defined in (1) above, and groups of formulae
R.sup.13 --(CH.sub.2).sub.m --CO-- and Het--CO-- where R.sup.13, m
and Het are as defined in (1) above; and
R.sup.12 represents any one of the groups or atoms defined for
R.sup.3 and R.sup.11 or a C.sub.1 -C.sub.5 alkyl groups or a
C.sub.1 -C.sub.3 alkyl group having at least one substituent
selected from the group consisting of substituents (f) defined in
(1) above.
(3) Compounds as defined in (1) above, where:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
(1);
R.sup.3, R.sup.6, R.sup.7 and R.sup.12 are independently selected
from the group consisting of hydrogen atoms, C.sub.1 -C.sub.5 alkyl
groups, C.sub.1 -C.sub.5 alkyl groups substituted by a group of
formula --COOR.sup.8a where R.sup.8a is as defined in (1) above,
C.sub.2 -C.sub.5 hydroxyalkyl groups, C.sub.1 -C.sub.5 alkyl groups
substituted by a C.sub.1 -C.sub.5 alkoxy group, C.sub.2 -C.sub.5
alkyl groups substituted by a group of formula --O--CO--R.sup.53
where R.sup.53 is as defined in (1) above and C.sub.1 -C.sub.3
alkyl groups substituted by a single substituent selected from the
group consisting of substituents (h) defined in (1) above; and
R.sup.11 represents a hydrogen atom, an acetyl group or a benzoyl
group; or
R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group, a C.sub.1 -C.sub.10 alkyl group having at least one
substituent selected from the group consisting of substituents (k),
a C.sub.2 -C.sub.6 alkanoyl group, a C.sub.2 -C.sub.10 alkanoyl
group having at least one substituent selected from the group
consisting of substituents (1), a C.sub.3 -C.sub.5 alkenoyl group,
a C.sub.3 -C.sub.5 alkenoyl group having at least one substituent
selected from the group consisting of substituents (1), a benzoyl
group, a benzoyl group having at least one substituent selected
from the group consisting of substituents (m), a pyridinecarbonyl
group, a furoyl group, a thenoyl group or a pyridinecarbonyl,
furoyl or thenoyl group having at least one substituent selected
from the group consisting of C.sub.1 -C.sub.5 alkyl groups;
said substituents (k) are selected from the group consisting of
hydroxy groups, phenyl groups, phenyl groups having at least one
substituent selected from the group consisting of substituents (m),
C.sub.2 -C.sub.5 alkanoyloxy groups, C.sub.2 -C.sub.10 alkanoyloxy
or C.sub.3 -C.sub.10 alkenoyloxy groups substituted by a group of
formula --COOR.sup.8a where R.sup.8a is as defined in (1) above,
C.sub.3 -C.sub.10 alkenoyloxy groups substituted by a phenyl group
where the phenyl group is unsubstituted or has at least one
substituent selected from the group consisting of substituents (m),
benzoyloxy groups, benzoyloxy groups having at least one
substituent selected from the group consisting of substituents (m),
groups of formula --COOR.sup.8a where R.sup.8a is as defined in (1)
above and substituents (h) as defined in (1) above;
said substituents (1) are selected from the group consisting of
phenyl groups, carboxy groups, alkoxycarbonyl groups where the
alkoxy part is C.sub.1 -C.sub.5 and benzyloxycarbonyl groups;
and
said substituents (m) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups,
halogen atoms and trifluoromethyl groups. PG,35
(4) Compounds of formula (I) in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, ethyl, isobutyl, pentyl, hexyl,
3,3-dimethylbutyl, heptyl, 4,4-dimethylpentyl, octyl,
5,5-dimethylhexyl, nonyl and 3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkanoyl
group, a C.sub.3 -C.sub.10 alkenoyl group, a substituted C.sub.1
-C.sub.10 alkanoyl or C.sub.3 -C.sub.10 alkenoyl group having at
least one substituent selected from the group consisting of
substituents (f) defined in (1) above, a benzoyl group, a benzoyl
group having at least one substituent selected from the group
consisting of substituents (n), an aralkanoyl group of formula
R.sup.15 --(CH.sub.2).sub.m --CO--
where R.sup.15 represents a phenyl group or a phenyl group having
at least one substituent selected from the group consisting of
substituents (n), and m is an integer from 1 to 5,
a pyridinecarbonyl group, a furoyl group, a thenoyl group, a
C.sub.1 -C.sub.3 alkyl group, a C.sub.1 -C.sub.3 alkyl group
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in (1) above, a C.sub.2 -C.sub.3 hydroxyalkyl group, a
C.sub.1 -C.sub.5 alkyl group substituted by a C.sub.1 -C.sub.5
alkoxy group, a C.sub.2 -C.sub.5 alkyl group substituted by a
C.sub.2 -C.sub.4 alkanoyloxy or a benzoyloxy group or a methyl
group having a single substituent selected from the group
consisting of substituents (h);
said substituents (n) are selected from the group consisting of
C.sub.1 -C.sub.5 alkyl groups, C.sub.1 -C.sub.5 alkoxy groups and
halogen atoms;
R.sup.4 represents a C.sub.1 -C.sub.10 alkyl group;
R.sup.5 represents a hydrogen atom or a C.sub.1 -C.sub.3 alkyl
group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.3 alkyl groups,
C.sub.1 -C.sub.3 alkyl groups substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined in (1) above, C.sub.2
-C.sub.3 hydroxyalkyl groups, C.sub.1 -C.sub.5 alkyl groups
substituted by a C.sub.1 -C.sub.5 alkoxy groups, C.sub.2 -C.sub.5
alkyl groups substituted by a C.sub.2 -C.sub.4 alkanoyloxy or a
benzoyloxy group, and methyl groups substituted by a single
substituent selected from the group consisting of substituents
(h);
Ar represents a o-phenylene, m-phenylene or p-phenylene group or a
pyridine-diyl group which is attached to the part of said compound
of formula (I) of formula --(CH.sub.2).sub.n --O-- at its
2-position and is attached to the --CH.sub.2 -thiazolidine group at
its 5- or 6-position, said phenylene and pyridine-diyl groups being
unsubstituted or having a methyl substituent;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>CH--OR.sup.11 or >C.dbd.N--OR.sup.12, where:
R.sup.11 represents a hydrogen atom or any one of the acyl groups
defined above for R.sup.3 ; and
R.sup.12 represents a benzyl group, any one of the groups or atoms
defined above for R.sup.3, a pyridinecarbonyl group or a
pyridinecarbonyl group having at least one substituent selected
from the group consisting of C.sub.1 -C.sub.5 alkyl groups;
and U represents
(i) where W represents a group of formula --CH.sub.2 --,
>C.dbd.O, >CH--OR.sup.11 or >C.dbd.N--OR.sup.12, a group
of formula --CH.sub.2 --,
(ii) with W, a group of formula --CH.dbd.CH--, or
(iii) where W represents a group of formula >C.dbd.O, with
R.sup.1 and the carbon atom to which R.sup.1 is attached, a group
of formula --CH.dbd.C>.
(5) Compounds as defined in (4) above, where:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
(4) above;
R.sup.6 and R.sup.7 are both hydrogen atoms;
R.sup.3 and R.sup.11 are independently selected from the group
consisting of hydrogen atoms, C.sub.1 -C.sub.10 alkanoyl groups,
C.sub.3 -C.sub.10 alkenoyl groups, C.sub.1 -C.sub.10 alkanoyl or
C.sub.3 -C.sub.10 alkenoyl groups having at least one substituent
selected from the group consisting of substituents (f) defined
above, benzoyl groups, benzoyl groups having at least one
substituent selected from the group consisting of substituents (n)
defined in (4) above, groups of formula R.sup.15 --(CH.sub.2).sub.m
--CO-- where R.sup.15 and m are as defined in (4) above,
pyridinecarbonyl groups, furoyl groups and thenoyl groups; and
R.sup.12 represents a hydrogen atom, a methyl group, a benzyl
group, a t-butoxycarbonylmethyl group or any one of the acyl groups
defined above for R.sup.3 and R.sup.11.
(6) Compounds as defined in (4) above, where:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar, W and U are as defined in
(4) above;
R.sup.3, R.sup.6 and R.sup.7 are independently selected from the
group consisting of C.sub.1 -C.sub.3 alkyl groups, C.sub.1 -C.sub.3
alkyl groups substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in (1) above, C.sub.2 -C.sub.3 hydroxyalkyl
groups, C.sub.1 -C.sub.5 alkyl groups substituted by a C.sub.1
-C.sub.5 alkoxy group, C.sub.2 -C.sub.5 alkyl groups substituted by
a C.sub.2 -C.sub.4 alkanoyloxy or a benzoyloxy group, and methyl
groups having a single substituent selected from the group
consisting of substituents (h) defined in (1) above;
R.sup.11 represents a hydrogen atom;
R.sup.12 represents a hydrogen atom, a C.sub.1 -C.sub.3 alkyl group
having at least one substituent selected from the group consisting
of substituents (o), a C.sub.2 -C.sub.4 alkanoyl group, a C.sub.2
-C.sub.4 alkanoyl group substituted by a group of formula
--COOR.sup.8a where R.sup.8a is as defined in (1) above, an
acryloyl group, acryloyl group having a .beta.-substituent selected
from the group consisting of substituents (f) defined above, a
benzoyl group, a benzoyl group having at least one substituent
selected from the group consisting of substituents (q), a
pyridinecarbonyl group, a pyridinecarbonyl group having at least
one substituent selected from the group consisting of C.sub.1
-C.sub.5 alkyl groups or any one of the groups defined above for
R.sup.3, R.sup.6 and R.sup.7 ;
said substituents (o) are selected from the group consisting of
carboxy groups and alkoxycarbonyl groups where the alkoxy part is
C.sub.1 -C.sub.5 ; and
said substituents (q) are selected from the group consisting of
methyl groups, ethyl groups, methoxy groups and ethoxy groups.
(7) Compounds of formula (I) in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a group
of formula R.sup.16 OOC(CH.sub.2).sub.m CO--
where R.sup.16 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group and m is an integer from 1 to 5,
a cis- or trans- group of formula R.sup.17 OOC.CH.dbd.CH--CO--
where R.sup.17 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group or a benzyl group,
2-, 3- or 4-pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in (1) above;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.3 alkyl groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in (1) above;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>C.dbd.N--OH, >C.dbd.N--OCH.sub.2 COOH or
>C.dbd.N--OCOR.sup.18
where R.sup.18 represents a C.sub.1 -C.sub.5 alkyl group; and
U represents a group of formula --CH.sub.2 --.
(7-a) Compounds of formula (I) in which:
R.sup.1 represents an alkyl group selected from the group
consisting of hexyl, heptyl, octyl, nonyl and 3,7-dimethyloctyl
groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.C.sub.5
alkanoyl group, C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group,
a group of formula R.sup.16 OOC(CH.sub.2).sub.m CO--
where R.sup.16 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group and m is an integer from 1 to 5,
a cis- or trans- group of formula R.sup.17 OOC.CH.dbd.CH--CO--
where R.sup.17 represents a hydrogen atom, C.sub.1 -C.sub.5 alkyl
group or a benzyl group,
2-, 3- or 4-pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in (1) above;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.3 alkyl groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in (1) above;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O or
>C.dbd.N--OR.sup.12
where R.sup.12 is as defined in (9) below or represents a C.sub.1
-C.sub.5 alkyl group or a C.sub.1 -C.sub.5 alkyl group substituted
by a phenyl group where the phenyl group is unsubstituted or has at
least one substituent selected from the group consisting of
substituents (n) as defined in (4) above; and
U represents a group of formula --CH.sub.2 --.
(7-b) Compounds of formula (I) in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a group
of formula R.sup.16 OOC(CH.sub.2).sub.m CO--
where R.sup.16 represents a hydrogen atom or a C.sub.1 -C.sub.5
alkyl group and m is an integer from 1 to 5,
a cis- or trans- group of formula R.sup.17 OOC.CH.dbd.CH--CO--
where R.sup.17 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkyl
group or a benzyl group,
a 2-, 3- or 4-pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in (1) above;
R.sup.4 represents an alkyl group selected from the group
consisting of hexyl, heptyl, octyl, 1,1,3,3-tetramethylbutyl,
1,1-dimethylbutyl and 1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are independently selected from the group
consisting of hydrogen atoms and C.sub.1 -C.sub.3 alkyl groups
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in (1) above;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O or
>C.dbd.N--OR.sup.12
where R.sup.12 is as defined in (9) below or represents a C.sub.1
-C.sub.5 alkyl group or a C.sub.1 -C.sub.5 alkyl group substituted
by a phenyl group where the phenyl group is unsubstituted or has at
least one substituent selected from the group consisting of
substituents (n) as defined in (4) above; and
U represents a group of formula --CH.sub.2 --.
(7-c) Compounds of formula (I) in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents C.sub.1 -C.sub.3 alkyl group substituted by a
group of formula --COOR.sup.8a
where R.sup.8a is as defined in (1) above;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are both hydrogen atoms;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>C.dbd.N--OH, or >C.dbd.N--O--(C.sub.1 -C.sub.3
alkyl)--COOR.sup.8a where R.sup.8a is as defined in (1) above;
U represents a group of formula --CH.sub.2 --; and
n is 1 or 2.
(7-d) Compounds of formula (I) in which:
R.sup.1 represents an alkyl group selected from the group
consisting of methyl, isobutyl, hexyl, heptyl, octyl, nonyl and
3,7-dimethyloctyl groups;
R.sup.2 represents a hydrogen atom or a methyl group;
R.sup.3 represents --CH.sub.2 --COO(C.sub.1 -C.sub.5 alkyl)
group;
R.sup.4 represents an alkyl group selected from the group
consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, 1,1,3,3-tetramethylbutyl, 1,1-dimethylbutyl and
1,1-dimethylpropyl groups;
R.sup.5 represents a hydrogen atom or a methyl group;
R.sup.6 and R.sup.7 are both hydrogen atoms;
Ar represents a p-phenylene group, a m-phenylene group having a
methyl group at the position ortho to the position of attachment to
the group of formula --(CH.sub.2).sub.n --O-- or a pyridine-diyl
group attached to said group of formula --(CH.sub.2).sub.n --O-- at
the 2-position and to the --CH.sub.2 -thiazolidine group at the
5-position;
W represents a group of formula --CH.sub.2 --, >C.dbd.O,
>C.dbd.N--OH, or >C.dbd.N--O--(C.sub.1 -C.sub.3
alkyl)--COO(C.sub.1 -C.sub.5 alkyl);
U represents a group of formula --CH.sub.2 --; and
n is 2 or 2.
(8) Compounds as defined in (7) above, where:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar and U are as defined in (7)
above;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.5 alkanoyl
group, a C.sub.3 -C.sub.5 alkenoyl group, a cinnamoyl group, a
group of formula R.sup.16 OOC(CH.sub.2).sub.m CO-- where R.sup.16
and m are as defined in (7) above, a cis or trans- group of formula
R.sup.17 OOC.CH.dbd.CH--CO-- where R.sup.17 is as defined in (7)
above, or a 2-, 3- or 4-pyridinecarbonyl group;
R.sup.6 and R.sup.7 are both hydrogen atoms;
W represents a group of formula >C.dbd.NOR.sup.12 where R.sup.12
is as defined in (9) below; and
n is 1 or 2.
(9) Compounds as defined in (7) above, where:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar and U are as defined in (7)
above;
R.sup.3, R.sup.6 and R.sup.7 are independently selected from the
group consisting of C.sub.1 -C.sub.3 alkyl groups substituted by a
group of formula --COOR.sup.8a where R.sup.8a is as defined in (1)
above;
W represents a group of formula >CH.sub.2, >C.dbd.O or
>C.dbd.NOR.sup.12 ;
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH--COOR.sup.8a where R.sup.8a is as defined in (1)
above, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group or any one of the groups defined above for
R.sup.3, R.sup.6 and R.sup.7 ; and
n is 1 or 2.
(9-a) Compounds as defined in (7) above, where:
R.sup.1, R.sup.2, R.sup.4, R.sup.5, Ar and U are as defined in (7)
above;
R.sup.3 represents a hydrogen atom, a C.sub.1 -C.sub.10 alkanoyl
group, a C.sub.3 -C.sub.10 alkenoyl group, a C.sub.1 -C.sub.10
alkanoyl or C.sub.3 -C.sub.10 alkenoyl group having at least one
substituent selected from the group consisting of substituents (f),
an arylcarbonyl group as defined in (1) above, a group of formula
R.sup.13 --(CH.sub.2).sub.m --CO-- or Het--CO-- where R.sup.13, m
and Het are as defined in (1) above or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in (1) above;
R.sup.6 represents a C.sub.1 -C.sub.3 alkyl group substituted by a
group of formula --COOR.sup.8a where R.sup.8a is as defined in (1)
above;
R.sup.7 represents a hydrogen atom or a C.sub.1 -C.sub.3 alkyl
group substituted by a group of formula --COOR.sup.8a where
R.sup.8a is as defined in (1) above;
W represents a group of formula >CH.sub.2, >C.dbd.O or
>C.dbd.NOR.sup.12, where
R.sup.12 represents a hydrogen atom, a group of formula
--(CH.sub.2).sub.3 COOR.sup.8a, --CH.sub.2 COOR.sup.8a,
--C(CH.sub.3).sub.2 COOR.sup.8a, --COCH.sub.2 CH.sub.2 COOR.sup.8a
or --CO--CH.dbd.CH --COOR.sup.8a where R.sup.8a is as defined in
(1) above, an acetyl group, a cinnamoyl group, a benzoyl group, a
pyridinecarbonyl group or a C.sub.1 -C.sub.3 alkyl group
substituted by a group of formula --COOR.sup.8a where R.sup.8a is
as defined in (1) above; and
n is 1 or 2.
Specific examples of compounds of the invention are given in the
following Tables 1-26, referring to the formula (I-1) to (I-26). In
the Tables, the following abbreviations are used:
______________________________________ Ac acetyl Boz benzoyl Bu
butyl .sub.- iBu isobutyl .sub.- tBu t-butyl Bz benzyl Dc decyl
3,3-DMB 3,3-dimethylbutyl 5,5-DMH 5,5-dimethylhexyl 3,7-DMO
3,7-dimethyloctyl 7,7-DMO 7,7-dimethyloctyl Et ethyl Hp heptyl Hx
hexyl Hxd hexadecyl Ic icosyl Me methyl Mor morpholino Nn nonyl Oc
octyl Ocd octadecyl Ph phenyl Phn phenylene Pip piperidino Piz
piperazinyl Pn pentyl .sub.- iPn isopentyl -nPn neopentyl Pr propyl
.sub.- iPr isopropyl Pydi pyridine-diyl Pyl pyrrolidinyl Pyr
pyridyl TMB 1,1,3,3-tetramethylbutyl Trd tridecyl
______________________________________
In the case of the divalent group represented by Ar, where
appropriate, the number given first is the position of attachment
of that group to the group represented by --(CH.sub.2).sub.n --O--
in the compound of formula (I), whilst the number given second is
the position of attachment of that group to the --CH.sub.2
-thiazolidine group.
Compounds of formula (I-1): ##STR3## are as defined in Table 1:
TABLE 1
__________________________________________________________________________
Cpd. No. R.sup.3 W Ar
__________________________________________________________________________
1 H ##STR4## 6-Me-1,3-Phn 2 Ac ##STR5## 6-Me-1,3-Phn 3 H ##STR6##
6-Me-1,3-Phn 4 H ##STR7## 6-Me-1,3-Phn 5 H ##STR8## 2,5-Pydi 6 H
##STR9## 2,5-Pydi 7 Ac ##STR10## 2,5-Pydi 8 H ##STR11## 2,5-Pydi 9
H ##STR12## p-Phn 10 H ##STR13## p-Phn 11 Ac ##STR14## p-Phn 12 Boz
##STR15## p-Phn 13 3-PyrCO ##STR16## p-Phn 14 H ##STR17## p-Phn 15
H ##STR18## p-Phn 16 H ##STR19## p-Phn 17 H ##STR20## p-Phn 18 Ac
##STR21## p-Phn 19 H ##STR22## p-Phn 20 H ##STR23## p-Phn 21 H
##STR24## p-Phn 22 Me(CH.sub.2).sub.14 CO ##STR25## p-Phn 23
HOOC(CH.sub.2).sub.2 CO ##STR26## p-Phn 24 HOOCCHCHCO-(cis)
##STR27## p-Phn 25 HOOC(CH.sub.2).sub.2 CO ##STR28## p-Phn 26
HOOC(CH.sub.2).sub.3 CO ##STR29## p-Phn 27 HOOC(CH.sub.2).sub.2 CO
##STR30## p-Phn 28 HOOC(CH.sub.2).sub.2 CO ##STR31## 2,5-Pydi 29
HOOC(CH.sub.2).sub.2 CO ##STR32## p-Phn 30 HOOC(CH.sub.2).sub.2 CO
##STR33## 2,5-Pydi
__________________________________________________________________________
Compounds of formula (I-2): ##STR34## are as defined in Table
2:
TABLE 2 ______________________________________ Cpd. No. R.sup.3 W
Ar ______________________________________ 31 H ##STR35## 6-Me-1,3-
Phn 32 H ##STR36## 6-Me-1,3- Phn 33 H ##STR37## 6-Me-1,3- Phn 34 H
##STR38## 2,5-Pydi 35 Ac ##STR39## 2,5-Pydi 36 H ##STR40## 2,5-Pydi
37 Ac ##STR41## 2,5-Pydi 38 H ##STR42## 2,5-Pydi 39 H ##STR43##
p-Phn 40 Ac ##STR44## p-Phn 41 Boz ##STR45## p-Phn 42 3-PyrCO
##STR46## p-Phn 43 H ##STR47## p-Phn 44 H ##STR48## p-Phn 45 H
##STR49## p-Phn 46 H ##STR50## p-Phn 47 H ##STR51## p-Phn 48 H
##STR52## p-Phn 49 H ##STR53## p-Phn 50 HOOC(CH.sub.2).sub.6 CO
##STR54## m-Phn ______________________________________
##STR55##
TABLE 3
__________________________________________________________________________
Cpd. No. R.sup.1 R.sup.3 -n W Ar
__________________________________________________________________________
51 me H 1 p-Phn 52 Me H 1 ##STR56## p-Phn 53 Me H 1 ##STR57## p-Phn
54 Me H 2 ##STR58## p-Phn 55 Me H 1 ##STR59## 6-Me-1,3-Phn 56 Me Ac
1 ##STR60## p-Phn 57 Me Ac 1 ##STR61## p-Phn 58 Me H 1 ##STR62##
6-Me-1,3-Phn 59 Me H 2 ##STR63## 6-Me-1,3-Phn 60 Me H 1 ##STR64##
2,5-Pydi 61 Me H 1 ##STR65## 2,5-Pydi 62 Me H 1 ##STR66## 2,5-Pydi
63 .sub.-iPr H 1 ##STR67## p-Phn 64 Bz H 1 ##STR68## p-Phn 65 Bz H
1 ##STR69## p-Phn 66 Bz H 1 ##STR70## 2,5-Pydi 67 Hx H 1 ##STR71##
p-Phn 68 Hx H 1 ##STR72## p-Phn 69 Hx H 1 ##STR73## p-Phn 70 Hx H 1
##STR74## 2,5-Pydi 71 3,3-DMB H 1 ##STR75## p-Phn 72 Hp H 1
##STR76## p-Phn 73 Oc H 1 ##STR77## p-Phn 74 Oc H 1 ##STR78## p-Phn
75 Oc H 1 ##STR79## p-Phn 76 Oc H 1 ##STR80## 2,5-Pydi 77 5,5-DMH H
1 ##STR81## p-Phn 78 5,5-DMH H 1 ##STR82## p-Phn 79 5,5-DMH H 1
##STR83## p-Phn 80 Dc H 1 ##STR84## p-Phn 81 Me HOOCCHCHCO 1
##STR85## p-Phn (trans)
__________________________________________________________________________
Compounds of formula (I-4): ##STR86## are as defined in Table
4:
TABLE 4 ______________________________________ Cpd. No. R.sup.1
R.sup.2 R.sup.4 R.sup.5 W ______________________________________ 82
Me .sub.-iPr .sub.-iPr Me ##STR87## 83 Et Me Me Me ##STR88## 84 Et
H .sub.-tBu H ##STR89## 85 Pr Me Me Me ##STR90## 86 .sub.-iBu Me Me
Me ##STR91## 87 Bz Me Me Me ##STR92## 88 1-MeHx H .sub.-tBu H
##STR93## 89 Oc Me Me Me ##STR94## 90 Oc Me Me Me ##STR95## 91 Oc
Me Me Me ##STR96## 92 Oc H .sub.-tBu H ##STR97## 93 5,5-DMH Me Me
Me ##STR98## 94 Dc Me Me Me ##STR99##
______________________________________
Compounds of formula (I-5): ##STR100## are as defined in Table
5:
TABLE 5 ______________________________________ Cpd. No. R.sup.1
R.sup.2 R.sup.4 R.sup.5 W ______________________________________ 95
Et .sub.-iPr .sub.-iPr H ##STR101## 96 Bz Me Me Me ##STR102## 97 Bz
Me Me Me ##STR103## 98 2-OMeBz H .sub.-tBu H ##STR104## 99 Hx Me Me
Me ##STR105## 100 Hx Me Me Me ##STR106## 101 Hx Me Me Me ##STR107##
102 Hx H .sub.-tBu H ##STR108## 103 Hx H .sub.-tBu H ##STR109## 104
Hx H .sub. -tBu H ##STR110## 105 3,3-DMB H .sub.-tBu H ##STR111##
106 Hp Me Me Me ##STR112## 107 Hp H .sub.-tBu H ##STR113## 108 Oc
Me Me Me ##STR114## 109 Oc Me Me Me ##STR115## 110 Oc Me Me Me
##STR116## 111 5,5-DMH Me Me Me ##STR117## 112 5,5-DMH Me Me Me
##STR118## 113 5,5-DMH H .sub.-tBu H ##STR119## 114 Dc Me Me Me
##STR120## ______________________________________ ##STR121##
TABLE 6 ______________________________________ Cpd. No. R.sup.1
R.sup.2 R.sup.4 R.sup.5 W n ______________________________________
115 .sub.-iPr H .sub.-tBu H 1 116 Bz Me Me Me ##STR122## 1 117 Bz
Me Me Me ##STR123## 1 118 .sub.-iBu Me Me Me ##STR124## 1 119 Bz H
.sub.-tBu H ##STR125## 1 120 4-MeBz H Me H ##STR126## 1 121 3-ClBz
.sub.-iPr .sub.-iPr H ##STR127## 1 122 2-PhEt Me Me Me ##STR128## 2
123 Hx Me Me Me ##STR129## 1 124 Hx Me Me Me ##STR130## 1 125 Hx Me
Me Me ##STR131## 1 126 Hx H .sub.-tBu H ##STR132## 1 127 Hx H
.sub.-tBu H ##STR133## 1 128 Hx H .sub.-tBu H ##STR134## 1 129
1-MePn Me Me Me ##STR135## 1 130 3,3-DMB Me Me Me ##STR136## 1 131
3,3-DMB Me Me Me ##STR137## 1 132 3,3-DMB Me Me Me ##STR138## 1 133
3,3-DMB H .sub.-tBu H ##STR139## 1 134 1-EtBu Me Me Me ##STR140## 2
135 3-MePn .sub.-iPr .sub.-iPr H ##STR141## 1 136 Hp Me Me Me
##STR142## 1 137 Hp Me Me Me ##STR143## 1 138 Hp Me Me Me
##STR144## 1 139 Hp H .sub.-tBu H ##STR145## 1 140 Hp H .sub.-tBu H
##STR146## 1 141 4,4-diMePn Me Me Me ##STR147## 1 142 Oc Me Me Me
##STR148## 1 143 Oc Me Me Me ##STR149## 1 144 Oc Me Me Me
##STR150## 1 145 Oc H .sub.-tBu H ##STR151## 1 146 Oc H .sub.-tBu H
##STR152## 1 147 Oc H .sub.-tBu H ##STR153## 1 148 5,5-DMH Me Me Me
##STR154## 1 149 5,5-DMH Me Me Me ##STR155## 1 150 5,5-DMH Me Me Me
##STR156## 1 151 5,5-DMH H .sub.-tBu H ##STR157## 1 152 5,5-DMH H
.sub.-tBu H ##STR158## 1 153 5,5-DMH H .sub.-tBu H ##STR159## 1 154
Nn Me Me Me ##STR160## 1 155 Dc Me Me Me ##STR161## 1 156 Dc H
.sub.-tBu H ##STR162## 1 157 1-MeNn Me Me H ##STR163## 1 158
3,7-DMO Me Me Me ##STR164## 1 159 3,7-DMO Me Me Me ##STR165## 1 160
3,7-DMO Me Me Me ##STR166## 1 161 3,7-DMO H .sub.-tBu H ##STR167##
1 162 3,7-DMO H .sub.-tBu H ##STR168## 1 163 7,7-DMO Me Me Me
##STR169## 1 164 7,7-DMO Me Me Me ##STR170## 1
______________________________________ ##STR171##
TABLE 7
__________________________________________________________________________
Cpd. No. R.sup.1 R.sup.2 R.sup.3 R.sup.5 W Ar n
__________________________________________________________________________
165 2-(3-OEtPh)Et H H H 2-Me-1,4-Phn 1 166 Hx Me H H ##STR172##
3-Me-1,4-Phn 1 167 Oc Me Ac Me ##STR173## p-Phn 1 168 Oc Me Ac Me
##STR174## p-Phn 1 169 5,5-DMH Me Ac Me ##STR175## 2,5-Pydi 1 170
3,7-DMO Me Ac Me ##STR176## p-Phn 1 171 7,7-DMO Me Ac Me ##STR177##
p-Phn 1 172 Pr Me EtOOC(CH.sub.2).sub.2 CO Me ##STR178## p-Phn 1
173 Oc Me HOOC(CH.sub.2).sub.4 CO Me ##STR179## p-Phn 2
__________________________________________________________________________
##STR180##
TABLE 8
__________________________________________________________________________
Cpd. No. R.sup.3 W' Ar -n
__________________________________________________________________________
174 H O p-Phn 1 175 Ac O p-Phn 1 176 H O p-Phn 2 177 Ac O p-Phn 2
178 H O p-Phn 3 179 Ac O p-Phn 3 180 Boz O p-Phn 1 181 H NOH p-Phn
1 182 Ac NOAc p-Phn 1 183 H NOH p-Phn 2 184 H NOH p-Phn 3 185 H O
6-Me-1,3-Phn 1 186 Ac O 6-Me-1,3-Phn 1 187 H O 6-Me-1,3-Phn 2 188 H
NOH 6-Me-1,3-Phn 1 189 Ac NOAc 6-Me-1,3-Phn 1 190 H O 2,5-Pydi 1
191 Ac O 2,5-Pydi 1 192 H O 2,5-Pydi 2 193 H NOH 2,5-Pydi 1 194
HOOC(CH.sub.2).sub.2 CO-- O p-Phn 1 195 HOOCCH.dbd.CHCO-(cis) O
p-Phn 1 196 HOOCCH.dbd.CHCO-(trans) O 2,5-Pydi 1 197
HOOC(CH.sub.2).sub.2 CO-- O p-Phn 2 198 HOOC(CH.sub.2).sub.2 CO--
NOH p-Phn 1 199 HOOC(CH.sub.2).sub.2 CO-- NOCH.sub.2 COOH p-Phn 1
200 HOOC(CH.sub.2).sub.2 CO-- NOCH.sub.2 COOH 2,5-Pydi 1 201
HOOC(CH.sub.2 ).sub.2 CO-- NOCH.sub.2 COO .sub.- tBu p-Phn 1 202
EtOOC(CH.sub.2).sub.6 CO-- NOCH.sub.2 COOEt p-Phn 1
__________________________________________________________________________
##STR181##
TABLE 9 ______________________________________ Cpd. No. R.sup.3 W'
Ar -n ______________________________________ 203 H O p-Phn 1 204 Ac
O p-Phn 1 205 H O p-Phn 2 206 Ac O p-Phn 2 207 H NOH p-Phn 1 208 H
O 6-Me-1,3-Phn 1 209 Ac O 6-Me-1,3-Phn 1 210 H O 2,5-Pydi 1 211 Ac
O 2,5-Pydi 1 212 Ac NOH 2,5-Pydi 1 213 HOOC(CH.sub.2).sub.2 CO-- O
p-Phn 1 ______________________________________
Compounds of formula (I-10): ##STR182## are as defined in Table
10:
TABLE 10 ______________________________________ Cpd. No. R.sup.3 W'
Ar -n ______________________________________ 214 H O p-Phn 1 215 Ac
O p-Phn 1 216 Ac NOH p-Phn 1 217 H NOH p-Phn 2 218 H O 6-Me-1,3-Phn
1 219 Ac O 6-Me-1,3-Phn 1 220 H O 6-Me-1,3-Phn 2 221 H NOH
6-Me-1,3-Phn 1 222 H O 2,5-Pydi 1 223 HOOC(CH.sub.2).sub.2 CO-- O
p-Phn 1 224 HOOC(CH.sub.2).sub.2 CO-- NOCH.sub.2 COOH 2,5-Pydi 1
______________________________________
Compounds of formula (I-11): ##STR183## are as defined in Table
11:
TABLE 11 ______________________________________ Cpd. No. R.sup.2
R.sup.3 R.sup.4 Ar ______________________________________ 225
.sub.- iPr H .sub.- iPr p-Phn 226 Me EtOOC(CH.sub.2).sub.4 CO-- Me
6-Me-1,3-Phn ______________________________________
Compounds of formula (I-12): ##STR184## are as defined in Table 12:
##STR185##
TABLE 12
__________________________________________________________________________
Cpd. No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 Ar
__________________________________________________________________________
227 Me Me H Me Me p-Phn 228 Me Me Ac Me Me p-Phn 229 Me Me Boz Me
Me p-Phn 230 Me Me H Me Me 6-Me-1,3-Phn 231 Me Me Ac Me Me
6-Me-1,3-Phn 232 Me Me H Me Me 2,5-Pydi 233 Me Me Ac Me Me 2,5-Pydi
234 Me H H .sub.- tBu H p-Phn 235 Me H Ac .sub.- tBu H p-Phn 236 Me
H H .sub.- tBu H 6-Me-1,3-Phn 237 Me H Ac .sub.- tBu H 6-Me-1,3-Phn
238 Me H H .sub.- tBu H 2,5-Pydi 239 Me H Ac .sub.- tBu H 2,5-Pydi
240 Me .sub.- iPr H .sub.- iPr H p-Phn 241 Me H H TMB H p-Phn 242
Me H H TMB H 6-Me-1,3-Phn 243 Me H H TMB H 2,5-Pydi 244 Et Me H Me
Me p-Phn 245 Pr H H .sub.- tBu H p-Phn 246 Pr H Ac .sub.- tBu H
p-Phn 247 .sub.- iPr H H TMB H p-Phn 248 .sub.- iBu Me H Me Me
p-Phn 249 .sub.- iBu Me Ac Me Me p-Phn 250 Bu H H .sub.- tBu H
p-Phn 251 .sub.- iBu H H TMB H p-Phn 252 -nPn Me H Me Me p-Phn 253
.sub.- iPn H H .sub.- tBu H p-Phn 254 Pn H H TMB H 2,5-Pydi 255 Hx
Me H Me Me p-Phn 256 Oc Me H Me Me p-Phn 257 Dc Me H Me Me p-Phn
258 3,7-DMO H H .sub.- tBu H p-Phn 259 7,7-DMO H H .sub.- tBu H
6-Me-1,3-Phn 260 3,7-DMO H H .sub.- tBu H 2,5-Pydi 261 7,7-DMO H H
TMB H p-Phn 262 Bz H H TMB H p-Phn 263 Me Me HOOC(CH.sub.2).sub.2
CO-- Me Me p-Phn 264 Me H HOOC(CH.sub.2).sub.2 CO-- .sub.- tBu H
p-Phn 265 Me H HOOC(CH.sub.2).sub.2 CO-- TMB H p-Phn
__________________________________________________________________________
Compounds of formula (I-13): ##STR186## are as defined in Table
13:
TABLE 13 ______________________________________ Cpd. No. R.sup.3 W
______________________________________ 266 Et ##STR187## 267
.sub.-iPr ##STR188## 268 Me ##STR189## 269 Pn ##STR190## 270 2-HOEt
##STR191## 271 2-HOEt ##STR192## 272 5-AcOPn ##STR193## 273 2-HOEt
##STR194## ______________________________________ ##STR195##
TABLE 14
__________________________________________________________________________
Cpd. No. R.sup.1 R.sup.2 R.sup.4 R.sup.5 R.sup.103 W Ar n r
__________________________________________________________________________
274 Me Me Me Me H p-Phn 1 1 275 Me Me Me Me Me ##STR196## p-Phn 1 1
276 Me Me Me Me Et ##STR197## p-Phn 1 1 277 Me Me Me Me .sub.-tBu
##STR198## p-Phn 1 1 278 Me Me Me Me H ##STR199## p-Phn 1 1 279 Me
Me Me Me Me ##STR200## p-Phn 1 1 280 Me Me Me Me Et ##STR201##
p-Phn 1 1 281 Me Me Me Me .sub.- iPr ##STR202## p-Phn 1 1 282 Me Me
Me Me .sub.-tBu ##STR203## p-Phn 1 1 283 Me Me Me Me H ##STR204##
p-Phn 1 1 284 Me Me Me Me H ##STR205## p-Phn 1 1 285 Me Me Me Me Et
##STR206## p-Phn 1 1 286 Me Me Me Me .sub.-tBu ##STR207## p-Phn 1 1
287 Me Me Me Me H ##STR208## p-Phn 1 1 288 Me Me Me Me Et
##STR209## p-Phn 1 1 289 Me Me Me Me .sub.-tBu ##STR210## p-Phn 1 1
290 Me Me Me Me H ##STR211## p-Phn 1 1 291 Me Me Me Me H ##STR212##
p-Phn 2 1 292 Me Me Me Me H ##STR213## p-Phn 1 2 293 Me Me Me Me H
##STR214## m-Phn 1 1 294 Me Me Me Me H ##STR215## 2,5-Pydi 1 1 295
Me Me Me Me H ##STR216## 2,5-Pydi 1 2 296 Me Me Me Me H ##STR217##
p-Phn 2 2 297 Me Me Me Me H ##STR218## 2,5-Pydi 1 1 298 Me Me Me Me
H ##STR219## 2,5-Pydi 3 3 299 Me Me Me Me H ##STR220## p-Phn 1 1
300 Me Me Me Me H ##STR221## p-Phn 1 1 301 Me H .sub.- tBu H H
##STR222## p-Phn 1 1 302 Me H .sub.-tBu H Et ##STR223## p-Phn 1 1
303 Me H .sub.-tBu H t-Bu ##STR224## p-Phn 1 1 304 Me H .sub.-tBu H
H ##STR225## p-Phn 1 1 305 Me H .sub.-tBu H H ##STR226## p-Phn 1 1
306 Me H .sub.-tBu H Et ##STR227## p-Phn 1 1 307 Me H .sub.-tBu H H
##STR228## p-Phn 1 1 308 Me H .sub.-tBu H H ##STR229## p-Phn 1 1
309 Me H .sub.-tBu H H ##STR230## 2,5-Pydi 1 1 310 Me H .sub.-tBu H
H ##STR231## 2,5-Pydi 1 1 311 Me H .sub.-tBu H H ##STR232##
2,5-Pydi 1 1 312 Et .sub.-iPr .sub.-iPr H Me ##STR233## p-Phn 1 1
313 Pr H Me H H ##STR234## p-Phn 1 1 314 .sub.-iPr H .sub.-tBu H H
##STR235## m-Phn 1 1 315 .sub.-iBu Me Me Me H ##STR236## p-Phn 1 1
316 .sub.-iBu Me Me Me H ##STR237## p-Phn 1 1 317 Oc Me Me Me H
##STR238## p-Phn 1 1 318 Oc Me Me Me H ##STR239## 2,5-Pydi 2 1 319
Me Me MeO MeO H ##STR240## p-Phn 1 1 320 Me Me MeO MeO H ##STR241##
p-Phn 1 1 321 Me H TMB H H ##STR242## p-Phn 1 1 322 Me H TMB H H
##STR243## p-Phn 1 1 323 Me H TMB H H ##STR244## p-Phn 1 1 324 Me H
TMB H H ##STR245## p-Phn 1 1 325 Bu H TMB H H ##STR246## 2,5-Pydi 1
3 326 5,5-DMH Me Me Me H ##STR247## p-Phn 1 1 327 Me Me Me Me Et
##STR248## p-Phn 1 5 328 Me Me Me Me H ##STR249## p-Phn 1 1
__________________________________________________________________________
TABLE 15
__________________________________________________________________________
Cpd. No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 W Ar n
__________________________________________________________________________
329 Me H HO(CH.sub.2).sub.2 OCOCH.sub.2 TMB H ##STR250## p-Phn 1
330 Pr H HO(CH.sub.2).sub.2 OCOCH.sub.2 .sub.-tBu H ##STR251##
p-Phn 1 331 Et H HO(CH.sub.2).sub.3 OCOCH.sub.2 Me H ##STR252##
p-Phn 1 332 Me Me HO(CH.sub.2).sub.5 OCOCH.sub.2 Me Me ##STR253##
p-Phn 1 333 Me Me MeO(CH.sub.2).sub.2 OCOCH.sub.2 Me Me ##STR254##
p-Phn 1 334 Me Me MeO(CH.sub.2).sub.2 OCOCH.sub.2 Me Me ##STR255##
p-Phn 1 335 Me Me MeO(CH.sub.2).sub.2 OCOCH.sub.2 Me Me ##STR256##
p-Phn 1 336 Me Me MeO(CH.sub.2).sub.2 OCOCH.sub.2 Me Me ##STR257##
p-Phn 1 337 Me H MeO(CH.sub.2).sub.2 OCOCH.sub.2 .sub.-tBu H
##STR258## p-Phn 1 338 Me H MeO(CH.sub.2).sub.2 OCOCH.sub.2
.sub.-tBu H ##STR259## p-Phn 1 339 Me H MeO(CH.sub.2).sub.2
OCOCH.sub.2 TMB H ##STR260## p-Phn 1 340 Me H MeO(CH.sub.2).sub.2
OCOCH.sub.2 TMB H ##STR261## p-Phn 1 341 Me Me MeO(CH.sub.2).sub.2
OCOCH.sub.2 Me Me ##STR262## p-Phn 1 342 Me Me MeO(CH.sub.2).sub.2
OCOCH.sub.2 Me Me ##STR263## 6-Me-1,3-Phn 1 343 3,3-DMB Me
EtO(CH.sub.2 ).sub.2 OCOCH.sub.2 Me Me ##STR264## p-Phn 1 344 Me H
.sub.-iPrO(CH.sub.2).sub.3 OCOCH.sub.2 Me H ##STR265## p-Phn 1 345
5,5-DMH H MeO(CH.sub.2).sub.5 OCOCH.sub.2 .sub.-iPr H ##STR266##
p-Phn 1 346 Me Me AcO(CH.sub.2).sub.2 OCOCH.sub.2 Me Me ##STR267##
2,5-Pydi 2 347 Bz Me BozO(CH.sub.2).sub.2 OCOCH.sub.2 Me Me
##STR268## p-Phn 1 348 Me Me MeO(CH.sub.2).sub.2
OCO(CH.sub.2).sub.2 MeO MeO ##STR269## p-Phn 1 349 7,7-DMO Me
MeO(CH.sub.2).sub.2 OCO(CH.sub.2).sub.3 Me Me ##STR270##
6-Me-1,3-Phn 1 350 Me Me MeO(CH.sub.2).sub.2 OCO(CH.sub.2).sub.5 Me
Me ##STR271## p-Phn 3 351 Me Me MeOOCCH(Me) Me Me ##STR272## p-Phn
1 352 Me Me MeOOCCH(Me)CH.sub.2 Me Me ##STR273## p-Phn 1 353 Me Me
MeOOCCMe.sub.2 Me Me ##STR274## p-Phn 1 354 Me Me EtOOCCMe.sub.2 Me
Me ##STR275## p-Phn 1 355 Me Me EtOOCCMe.sub.2 Me Me ##STR276##
p-Phn 1 356 Me Me EtOOCCMe.sub.2 Me Me ##STR277## p-Phn 1 357 Me Me
EtOOCCMe.sub.2 Me Me ##STR278## p-Phn 1 358 Me Me EtOOCCMe.sub.2 Me
Me ##STR279## p-Phn 1 359 Me H EtOOCCMe.sub.2 .sub.-tBu H
##STR280## p-Phn 1 360 Me H EtOOCCMe.sub.2 .sub. -tBu H ##STR281##
p-Phn 1 361 Me H EtOOCCMe.sub.2 .sub.-tBu H ##STR282## p-Phn 1 362
Me H EtOOCCMe.sub.2 .sub.-tBu H ##STR283## p-Phn 1 363 Me H
EtOOCCMe.sub.2 .sub.-tBu H ##STR284## p-Phn 1 364 Me Me
EtOOCCMe.sub.2 Me Me ##STR285## p-Phn 1 365 Me Me HOOCCMe.sub.2 Me
Me ##STR286## p-Phn 1 366 Me Me HOOCCMe.sub.2 Me Me ##STR287##
p-Phn 1 367 Me Me HOOCCMe.sub.2 Me Me ##STR288## p-Phn 1 368 Me Me
HOOCCMe.sub.2 Me Me ##STR289## p-Phn 1 369 Me Me HOOCCMe.sub.2 Me
Me ##STR290## p-Phn 1 370 Me Me HOOCCMe.sub.2 Me Me ##STR291##
p-Phn 1 371 Me H HOOCCMe.sub.2 .sub.-tBu H ##STR292## p-Phn 1 372
Me H HOOCCMe.sub.2 .sub.-tBu H ##STR293## p-Phn 1 373 Me H
HOOCCMe.sub.2 .sub.-tBu H ##STR294## p-Phn 1 374 Me H HOOCCMe.sub.2
TMB H ##STR295## p-Phn 1 375 Me H HOOCCMe.sub.2 TMB H ##STR296##
p-Phn 1 376 Me Me H.sub.2 NCOCH.sub.2 Me Me ##STR297## p-Phn 1 377
Me Me MeNHCOCH.sub.2 Me Me ##STR298## p-Phn 1 378 Me H Me.sub.2
NCOCH.sub.2 .sub.-tBu H ##STR299## p-Phn 1 379 Me Me
Et(Me)NCOCH.sub.2 Me Me ##STR300## p-Phn 1 380 Me Me MorCOCH.sub.2
Me Me ##STR301## p-Phn 1 381 Me Me 1-PipCOCH.sub.2 Me Me ##STR302##
p-Phn 1 382 Me Me 1-PylCOCH.sub.2 Me Me ##STR303## 6-Me-1,3-Phn 1
383 Me H 1-PizCOCH.sub.2 TMB H ##STR304## p-Phn 1 384 Me Me
4-Me-1-PizCOCH.sub.2 Me Me ##STR305## p-Phn 1 385 Me Me Me.sub.2
NCOCH.sub.2 CH.sub.2 Me Me ##STR306## p-Phn 2 386 Me Me Me.sub.2
NCOCMe.sub.2 Me Me ##STR307## p-Phn 1 387 Me Me Me.sub.2
NCO(CH.sub.2).sub.5 Me Me ##STR308## p-Phn 1
__________________________________________________________________________
TABLE 16
__________________________________________________________________________
Cpd. No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 W Ar n
__________________________________________________________________________
388 Me Me HOOCCH.sub.2 Me Me Oc ##STR309## p-Phn 1 389 Me H
EtOOCCH.sub.2 Me H 5,5-DMH ##STR310## p-Phn 3 390 Me Me MeOCH.sub.2
CH.sub.2 OCOCH.sub.2 Me Me Me ##STR311## p-Phn 1 391 Me Me
AcOCH.sub.2 CH.sub.2 OCOCH.sub.2 MeO MeO 2-MeOEt ##STR312##
2,5-Pydi 2 392 Me Me HOOCCMe.sub.2 Me Me Bu ##STR313## 5-Me-1,3-Phn
1 393 Me H HOOCCH.sub.2 CH.sub.2 TMB H 3,3-DMB ##STR314## p-Phn 1
394 Me Me H.sub.2 NCOCH.sub.2 Me Me Dc ##STR315## p-Phn 1 395
7,7-DMO H Et(Me)NCOCH.sub.2 .sub.-tBu H .sub.-iBu ##STR316## p-Phn
1 396 Me Me H Me Me Et ##STR317## p-Phn 1 397 3,3-DMB H Me TMB H Pr
##STR318## p-Phn 1 398 Me Me Ac Me Me .sub.-iPr ##STR319## p-Phn 1
399 Me H Me .sub.-tBu H Bu ##STR320## p-Phn 1 400 Me Me H Me Me
2-OHEt ##STR321## p-Phn 1
__________________________________________________________________________
TABLE 17
__________________________________________________________________________
Cpd No. R.sup.1 R.sup.2 R.sup.4 R.sup.5 R.sup.106 W Ar n p
__________________________________________________________________________
401 Me Me Me Me H ##STR322## p-Phn 1 1 402 Me Me Me Me Me
##STR323## p-Phn 1 1 403 Me Me Me Me Et ##STR324## p-Phn 1 1 404 Me
Me Me Me .sub.-tBu ##STR325## p-Phn 1 1 405 Me Me Me Me H
##STR326## p-Phn 1 1 406 Me Me Me Me Me ##STR327## p-Phn 1 1 407 Me
Me Me Me .sub.-iPr ##STR328## p-Phn 1 1 408 Me Me Me Me .sub.-tBu
##STR329## p-Phn 1 1 409 Me Me Me Me H ##STR330## p-Phn 1 1 410 Me
Me Me Me H ##STR331## p-Phn 1 1 411 Me Me Me Me .sub.-tBu
##STR332## p-Phn 1 1 412 Me Me Me Me H ##STR333## p-Phn 1 1 413 Me
Me Me Me H ##STR334## p-Phn 1 1 414 Me Me Me Me .sub.-tBu
##STR335## p-Phn 1 1 415 Me Me Me Me H ##STR336## p-Phn 2 1 416 Me
Me Me Me H ##STR337## p-Phn 1 2 417 Me Me Me Me H ##STR338## m-Phn
1 1 418 Me Me Me Me H ##STR339## 2,5-Pydi 1 1 419 Me Me Me Me H
##STR340## 2,5-Pydi 1 2 420 Me Me Me Me H ##STR341## p-Phn 2 2 421
Me Me Me Me H ##STR342## 2,5-Pydi 1 1 422 Me Me Me Me H ##STR343##
2,5-Pydi 3 3 423 Me Me Me Me H ##STR344## p-Phn 1 1 424 Me Me Me Me
H ##STR345## p-Phn 1 1 425 Me H .sub.-tBu H H ##STR346## p-Phn 1 1
426 Me H .sub.-tBu H .sub.-tBu ##STR347## p-Phn 1 1 427 Me H
.sub.-tBu H H ##STR348## p-Phn 1 1 428 Me H .sub.-tBu H H
##STR349## p-Phn 1 1 429 Me H .sub.-tBu H H ##STR350## p-Phn 1 1
430 Me H .sub.-tBu H H ##STR351## 2,5-Pydi 1 1 431 Me H .sub.-tBu H
H ##STR352## 2,5-Pydi 1 1 432 Me H .sub.-tBu H H ##STR353##
2,5-Pydi 1 1 433 Et .sub.-iPr .sub.-iPr H Me ##STR354## p-Phn 1 1
434 Pr H Me H H ##STR355## p-Phn 1 1 435 .sub.-iPr H .sub.-tBu H H
##STR356## m-Phn 1 1 436 .sub.-iBu Me Me Me H ##STR357## p-Phn 1 1
437 .sub.-iBu Me Me Me H ##STR358## p-Phn 1 1 438 Oc Me Me Me H
##STR359## p-Phn 1 1 439 Oc Me Me Me H ##STR360## 2,5-Pydi 2 1 440
Me Me MeO MeO H ##STR361## p-Phn 1 1 441 Me Me MeO MeO H ##STR362##
p-Phn 1 1 442 Me H TMB H H ##STR363## p-Phn 1 1 443 Me H TMB H H
##STR364## p-Phn 1 1 444 Me H TMB H H ##STR365## p-Phn 1 1 445 Me H
TMB H H ##STR366## p-Phn 1 1 446 Bu H TMB H H ##STR367## 2,5-Pydi 1
3
__________________________________________________________________________
##STR368##
TABLE 18 ______________________________________ Cpd No. R.sup.2
R.sup.3 R.sup.4 R.sup.5 W ______________________________________
447 Me Me Me Me 448 Me Ac Me Me ##STR369## 449 Me MeOCH.sub.2 Me Me
##STR370## 450 H Boz .sub.-tBu H ##STR371## 451 Me EtOOCCH.sub.2 Me
Me ##STR372## ______________________________________ ##STR373##
TABLE 19
__________________________________________________________________________
Cpd No. R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 W
__________________________________________________________________________
452 Me Ac Me Me CH.sub.2 COOH 453 Me Ac Me Me CH.sub.2 COOMe
##STR374## 454 Me Ac Me Me CH.sub.2 COOt-Bu ##STR375## 455 Me H Me
Me CMe.sub.2 COOH ##STR376## 456 H Ac .sub.-tBu H CMe.sub.2 COOH
##STR377## 457 Me H Me Me CMe.sub.2 COOEt ##STR378## 458 Me H Me Me
CH.sub.2 CONMe.sub.2 ##STR379## 459 Me H Me Me CH.sub.2
C)(4-Me-1-Piz) ##STR380## 460 Me HOOCCMe.sub.2 Me Me CH.sub.2 COOH
##STR381##
__________________________________________________________________________
Compounds of formulae (I-20), (I-21), (I-22), (I-23) and (I-24):
##STR382##
TABLE 20
__________________________________________________________________________
Cpd No. R.sup.1 R.sup.2 R.sup.4 R.sup.5 R.sup.103 R.sup.106 W Ar n
r p
__________________________________________________________________________
461 Me Me Me Me H H p-Phn 1 1 1 462 Me Me Me Me Et Et ##STR383##
p-Phn 1 1 1 463 Me Me Me Me .sub.-tBu .sub.-tBu ##STR384## p-Phn 1
1 1 464 Me Me Me Me H H ##STR385## p-Phn 1 1 1 465 Me Me Me Me Me
Me ##STR386## p-Phn 1 1 1 466 Me Me Me Me .sub.-tBu .sub.-tBu
##STR387## p-Phn 1 1 1 467 Me Me Me Me H H ##STR388## p-Phn 1 1 1
468 Me Me Me Me .sub.-tBu .sub.-tBu ##STR389## p-Phn 1 1 1 469 Me
Me Me Me H H ##STR390## p-Phn 1 1 1 470 Me Me Me Me H H ##STR391##
p-Phn 1 1 1 471 Me Me Me Me .sub.-tBu .sub.-tBu ##STR392## p-Phn 1
1 1 472 Me Me Me Me H H ##STR393## p-Phn 1 2 2 473 Me Me Me Me H H
##STR394## p-Phn 2 1 1 474 Me Me Me Me H H ##STR395## p-Phn 1 2 1
475 Me Me Me Me H H ##STR396## p-Phn 2 1 2 476 Me Me Me Me H H
##STR397## m-Phn 1 3 3 477 Me Me Me Me H H ##STR398## 2,5-Pydi 1 1
1 478 Me Me Me Me H H ##STR399## 2,5-Pydi 1 1 1 479 Me Me Me Me H H
##STR400## 2,5-Pydi 1 1 1 480 Me Me Me Me H H ##STR401## 2,5-Pydi 1
1 1 481 Me Me Me Me Et .sub.-iPr ##STR402## 2,5-Pydi 1 1 1 482 Me
Me Me Me H H ##STR403## 2,5-Pydi 3 2 2 483 Me Me Me Me H H
##STR404## 2,5-Pydi 1 2 2 484 Me H .sub.-tBu H H H ##STR405## p-Phn
1 1 1 485 Me H .sub.-tBu H Et Et ##STR406## p-Phn 1 1 1 486 Me H
.sub.-tBu H .sub.-tBu .sub.-tBu ##STR407## p-Phn 1 1 1 487 Me H
.sub.-tBu H H H ##STR408## p-Phn 1 1 1 488 Me H .sub.-tBu H
.sub.-tBu .sub.-tBu ##STR409## p-Phn 1 1 1 489 Me H .sub.-tBu H H H
##STR410## p-Phn 1 1 1 490 Me H .sub.-tBu H H H ##STR411## p-Phn 1
1 1 491 Me H .sub.-tBu H .sub. -tBu .sub.-tBu ##STR412## p-Phn 1 1
1 492 Me H .sub.-tBu H H H ##STR413## 2,5-Pydi 1 1 1 493 Et Me Me
Me H H ##STR414## p-Phn 1 2 2 494 Pr Me Me Me H H ##STR415## m-Phn
2 1 1 495 .sub.-iPr H Me H H H ##STR416## p-Phn 2 3 3 496 .sub.-iBu
Me Me Me H H ##STR417## 2,5-Pydi 1 1 1 497 Oc Me Me Me H H
##STR418## p-Phn 1 1 1 498 Me Me MeO MeO H H ##STR419## p-Phn 1 1 1
499 Me Me MeO MeO H H ##STR420## p-Phn 1 1 1 500 Me H TMB H H H
##STR421## p-Phn 1 1 1 501 Me H TMB H H H ##STR422## p-Phn 1 1 1
502 Me H TMB H H H ##STR423## p-Phn 1 1 1 503 Me H TMB H H H
##STR424## p-Phn 1 1 1 504 Me H TMB H H H ##STR425## 2,5-Pydi 1 1 1
__________________________________________________________________________
TABLE 21
__________________________________________________________________________
Cpd No. R.sup.2 R.sup.4 R.sup.5 R.sup.103 R.sup.106 R.sup.107 W Ar
r p q
__________________________________________________________________________
505 Me Me Me H H H ##STR426## p-Phn 1 1 1 506 Me Me Me Et Et Et
##STR427## p-Phn 1 1 1 507 Me Me Me .sub.-tBu .sub.-tBu .sub.-tBu
##STR428## p-Phn 1 1 1 508 Me Me Me H H H ##STR429## p-Phn 1 1 1
509 Me Me Me .sub.-tBu .sub.-tBu .sub.-tBu ##STR430## p-Phn 1 1 1
510 Me Me Me H H H ##STR431## p-Phn 1 1 1 511 Me Me Me .sub.-tBu
.sub.-tBu .sub.-tBu ##STR432## p-Phn 1 1 1 512 Me Me Me H H H
##STR433## p-Phn 1 1 1 513 Me Me Me Et Et Et ##STR434## p-Phn 1 1 1
514 Me Me Me H H H ##STR435## p-Phn 2 3 4 515 Me Me Me H H H
##STR436## 2,5-Pydi 1 1 1 516 Me Me Me H H H ##STR437## 2,5-Pydi 1
1 1 517 Me Me Me Et Et Et ##STR438## 2,5-Pydi 1 1 1 518 H t-Bu H H
H H ##STR439## p-Phn 1 1 1 519 H t-Bu H H H H ##STR440## p-Phn 1 1
1 520 H t-Bu H H H H ##STR441## p-Phn 1 1 1 521 H t-Bu H H H H
##STR442## 2,5-Pydi 1 1 1 522 H TMB H H H H ##STR443## p-Phn 1 1 1
523 H TMB H H H H ##STR444## p-Phn 1 1 1
__________________________________________________________________________
TABLE 22
__________________________________________________________________________
Cpd No. R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 W Ar n
__________________________________________________________________________
524 Me HOOCCMe.sub.2 Me Me CMe.sub.2 COOH CMe.sub.2 COOH ##STR445##
p-Phn 1 525 Me HOOCCMe.sub.2 Me Me CMe.sub.2 COOH CMe.sub.2 COOH
##STR446## 2,5-Pydi 1 526 Me HOOCCMe.sub.2 Me Me CMe.sub.2 COOH
CMe.sub.2 COOH ##STR447## p-Phn 1 527 Me HOOCCMe.sub.2 Me Me
CMe.sub.2 COOH CMe.sub.2 COOH ##STR448## p-Phn 1 528 H
HOOCCMe.sub.2 .sub.-tBu H CMe.sub.2 COOH CMe.sub.2 COOH ##STR449##
6-Me-1,3-Phn 2 529 Me H.sub.2 NCOCH.sub.2 Me Me CH.sub.2 CONH.sub.2
CH.sub.2 CONH.sub.2 ##STR450## p-Phn 1 530 Me MorCOCH.sub.2 Me Me
CH.sub.2 COMor CH.sub.2 COMor ##STR451## p-Phn 1 531 Me
HOOCCH.sub.3 Me Me CH.sub.2 CONH.sub.2 CH.sub.2 CONH.sub.2
##STR452## p-Phn 1 532 Me HOOCCMe.sub.2 Me Me CH.sub.2 COMor
CH.sub.2 COMor ##STR453## p-Phn 1
__________________________________________________________________________
TABLE 23
__________________________________________________________________________
Cpd No. R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 W.sub.1 Ar
__________________________________________________________________________
533 Me HOOCCH.sub.2 Me Me H H ##STR454## p-Phn 534 Me HOOCCH.sub.2
Me Me CH.sub.2 COOH H ##STR455## p-Phn 535 Me EtOOCCH.sub.2 Me Me
CH.sub.2 COOEt CH.sub.2 COOEt ##STR456## p-Phn 536 Me H Me Me
CH.sub.2 COOH H ##STR457## p-Phn 537 Me HOOCCMe.sub.2 Me Me H H
##STR458## p-Phn 538 H PipCOCH.sub.2 t-Bu H CH.sub.2 COPip H
##STR459## 2,5-Pydi
__________________________________________________________________________
TABLE 24
__________________________________________________________________________
Cpd. No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 R.sup.6 R.sup.7 Ar
__________________________________________________________________________
539 Me Me MeOCH.sub.2 CH.sub.2 OOCCH.sub.2 -- Me Me H H p-Phn 540
Me Me HOOCCH.sub.2 -- Me Me H H p-Phn 541 7,7-DMO H HOOCCMe.sub.2
-- .sub.- tBu H --CMe.sub.2 COOH --CMe.sub.2 COOH 2,5-Pydi 542 Me
Me MeOOCCH.sub.2 -- Me Me H H p-Phn 543 Me Me 2-HOEt Me Me H H
p-Phn 544 Bz H CH.sub.3 OCH.sub.2 -- TMB H --CMe.sub.2 COOEt
--CH.sub.2 COOt-Bu 6-Me-1,3-Phn 545 Me Me H Me Me --CH.sub.2 COOH
--CH.sub.2 COOH p-Phn
__________________________________________________________________________
Compounds of formula (I-25): ##STR460## are as defined in Table
25:
TABLE 25 ______________________________________ Cpd No. R.sup.1
R.sup.2 R.sup.4 R.sup.5 n W ______________________________________
546 Me Me Me Me 1 ##STR461## 547 Me Me Me Me 1 ##STR462## 548 Me H
.sub.-tBu H 1 ##STR463## 549 Me H .sub.-tBu H 1 ##STR464## 550 Me
Me Me Me 2 ##STR465## 551 Me H .sub.-tBu H 2 ##STR466## 552 Et Me
Me Me 1 ##STR467## 553 .sub.-iBu Me Me Me 1 ##STR468## 554
.sub.-iBu Me Me Me 1 ##STR469## 555 Pn Me Me Me 1 ##STR470## 556 H
Me Me Me 1 ##STR471## 557 Me H .sub.-iPr H 1 ##STR472## 558
.sub.-iBu H .sub.-tBu H 1 ##STR473## 559 Oc Me Me Me 1 ##STR474##
560 Oc Me Me Me 1 ##STR475## 561 Oc H .sub.-tBu H 1 ##STR476## 562
Oc H .sub.-tBu H 1 ##STR477## 563 Me H TMB H 1 ##STR478## 564 Me H
TMB H 2 ##STR479## 565 .sub.-iBu H TMB H 1 ##STR480## 566 Oc H TMB
H 1 ##STR481## ______________________________________
Compounds of formula (I-26): ##STR482## are as defined in Table
26:
TABLE 26 ______________________________________ Cpd. No. R.sup.2
R.sup.103 R.sup.4 R.sup.5 R.sup.106 W'
______________________________________ 546 Me H Me Me H
.dbd.NOCMe.sub.2 COOH 547 H H .sub.- tBu H H .dbd.NOCH.sub.2 COOH
548 Me H Me Me H .dbd.NOH 549 Me H Me Me H .dbd.H.sub.2 550 Me Et
Me Me Et .dbd.H.sub.2 ______________________________________
Of the compounds listed above, preferred compounds are Compounds
Nos. 5, 9, 10, 11, 12, 14, 15, 17, 23, 32, 39, 51, 52, 53, 56, 57,
118, 142, 159, 160, 174, 227, 274, 276, 278, 279, 280, 282, 284,
285, 287, 288, 301, 302, 305, 307, 401, 403, 405, 410, 412, 425,
428, 429, 461, 462, 464, 465, 467, 469, 484, 485, 487, 489, 490,
492, 505, 506, 508, 510, 512, 513, 518, 519, 520, 521, and 546. The
more preferred compounds are Compounds Nos. 9, 10, 11, 12, 17, 23,
51, 52, 53, 56, 57, 118, 142, 159, 160, 174, 274, 284, 401, 405,
410, 461, 464, 467, 508 and 510, and the most preferred compounds
are Compounds Nos. 9, 11, 142, 464, 467 and 510.
Also preferred are pharmaceutically acceptable salts of the above
compounds.
The compounds of the invention, which include those compounds
having no proviso, may be prepared by reacting a compound of
formula (II): ##STR483## [in which: R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, n and Ar are as defined above;
A represents a cyano group, a carboxy group, a C.sub.2 -C.sub.6
alkoxycarbonyl group, a carbamoyl group or a group of formula -COOM
where M represents a cation;
X represents a halogen atom;
R.sup.7a represents a hydrogen atom or an unsubstituted C.sub.1
-C.sub.10 alkyl group; and
W.sup.2 represents a methylene (--CH.sub.2 --) group or a carbonyl
(>C.dbd.O) group] with thiourea, which has the formula (III):
##STR484## to give a compound of formula (V): ##STR485## (in which:
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.71, n, Ar and
W.sup.2 are as defined above; and
Y represents an oxygen atom or an imino group).
This compound may immediately be hydrolized under the prevailing
reaction conditions; if it is not, then a separate hydrolysis step
is required, to hydrolize the imino group at the 2-position of the
thiazolidine ring and, where Y represents an imino group, hydrolize
that imino group also, to an oxygen atom, thereby giving the
compound of formula (IV): ##STR486## (in which R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.7a, n, Ar and W.sup.2 are as
defined above).
If necessary, subsequent steps may be carried out to replace
various of the substituent groups by other groups within the
definitions given above, employing the reactions described in more
detail hereafter.
Where A represents a C.sub.2 -C.sup.6 alkoxycarbonyl group (i.e.
the alkoxy part has from 1 to 5 carbon atoms), examples of such
groups include the methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropoxycarbonyl and butoxycarbonyl groups.
Where A represents a group of formula -COOM and M represents a
cation, the nature of the cation is not critical to the invention,
since it is eliminated in the course of the reaction. Preferably
the cation is a metal ion, such as a sodium, potassium, calcium or
aluminum ion, but it may also be an ammonium ion and other ions,
including ions derived from organic bases, are possible, although
not presently preferred.
X represents a halogen atom and, again, the nature of this is not
critical, since the atom is eliminated in the course of the
reaction. Most suitably, the halogen atom represented by X is a
chlorine, bromine or iodine atom.
The reaction of the compound of formula (II) with the thiourea is
preferably effected in the presence of a solvent. The nature of the
solvent is not critical, provided that it has no adverse effect
upon the reaction. Suitable solvents include, for example:
alcohols, such as methanol, ethanol, propanol, butanol and ethylene
glycol monomethyl ether; ethers, such as tetrahydrofuran or
dioxane; ketones, such as acetone; dimethyl sulfoxide; sulfones,
such as sulfolane; and amides, such as dimethylformamide.
There is no criticality as to the molar ratio of the compound of
formula (II) to the thiourea and so conventional criteria apply to
determine the most suitable proportions. Preferably the two
reagents are employed in equimolar amounts or the thiourea is
employed in excess, preferably a slight excess. The most suitable
ratio of thiourea to compound of formula (II) is from 1:1 to
2:1.
The reaction temperature is not critical to the invention, although
the optimum temperature will vary, depending upon the nature of the
reagents and the solvent employed. In general, we prefer to carry
out the reaction at the boiling point of the solvent or at a
temperature within the range from 80.degree. to 150.degree. C. The
time required for the reaction will vary, depending upon many
factors, notably the reaction temperature and the nature of the
reagents, but a period of from 1 to 20 hours will normally
suffice.
Where hydrolysis of the resulting compound of formula (V) is
required, this may be effected by heating the compound of formula
(V) in a suitable solvent in the presence of water and of an acid.
The nature of the solvent is not critical, provided that it has no
adverse effect upon the reaction and examples of suitable solvents
include: sulfolane; and alcohols, such as methanol, ethanol or
ethylene glycol monomethyl ether. Suitable acids include such
organic acids as acetic acid and such mineral acids as sulfuric
acid or hydrochloric acid. The amount of acid added is preferably
from 0.1 to 10 moles, more preferably from 0.2 to 3 moles, per mole
of the compound of formula (V). The water or aqueous solvent
employed in this hydrolysis is preferably added in stoichiometric
excess with respect of the compound of formula (V), preferably a
large excess. The reaction temperature is not particularly
critical, although we prefer to carry out the reaction at a
temperature of from 50.degree. to 100.degree. C., at which
temperature the reaction will normally be essentially complete
within a period of from 2 to 20 hours.
Where R.sup.3 in the compound of formula (V) represents an acyl
group, the hydrolysis step will often hydrolize this to a hydrogen
atom, giving a compound of formula (IVH): ##STR487## (in which
R.sup.1, R.sup.2 R.sup.4, R.sup.5, R.sup.7a n, Ar and W.sup.2 are
as defined above); however, depending upon the precise reaction
conditions and the nature of the acyl group represented by R.sup.3,
this hydrolysis may not take place or may take place to a limited
extent only, so that the acyl group is kept intact. Similarly,
other acyl groups within the compound of formula (V) may or may not
also be hydrolized.
Compounds of formula (IV) can exist in the following tautomeric
forms: ##STR488## although, for convenience, these are represented
by a single formula (IV) herein. It will be appreciated that
similar tautomeric forms exist in relation to the imino compound of
formula (V) and these likewise are shown herein by means of a
single formula only.
Those compounds of the invention which contain one or more carboxy
groups or which contain a phenolic hydroxy group [e.g. where
R.sup.3 represents a hydrogen atom, as in the compounds of formula
(IVH)] can form salts, in a conventional manner, with cations.
There is no particular restriction on the nature of the cations
employed to form such salts, except that, where the compounds of
the invention are to be used for therapeutic purposes, the
resulting salts should be pharmaceutically acceptable, which, as is
well-known in the art, means that the resulting salts should not
have a reduced activity (or unacceptably reduced activity) or an
increased toxicity (or unacceptably increased toxicity) as compared
with the parent compound. On the other hand, where the compounds
are to be used for non-therapeutic purposes, e.g. where they are to
be used as intermediates in the preparation of other compounds,
even this restriction does not apply. Suitable salts include, for
example: alkali metal salts, such as the sodium, potassium or
lithium salts; alkaline earth metal salts, such as the calcium or
magnesium salts; salts with other metals, especially trivalent
metals, for example salts with aluminum, iron, cobalt, nickel or
zinc; ammonium salts; salts with organic amines, for example the
triethylamine or cyclohexylamine salts; and salts with basic amino
acids, for example lysine or arginine.
Likewise, where the compounds of the invention contain a basic
group, they can form acid addition salts. As with the salts
mentioned above, where the compounds are to be used for therapeutic
purposes, the salts should be pharmaceutically acceptable but,
where they are to be used for non-therapeutic purposes, this
restriction does not apply. Suitable acids for use in producing
such salts include: inorganic acids, such as hydrochloric acid,
sulfuric acid, nitric acid or phosphoric acid; organic carboxylic
acids, such as acetic acid, tartaric acid, maleic acid, fumaric
acid, malic acid, glutamic acid or aspartic acid; and organic
sulfonic acids, such as p-toluenesulfonic acid or methanesulfonic
acid.
Furthermore, compounds of formula (IVH) can be converted into a
corresponding ester by reaction with an acylating agent, normally
an organic acid or reactive derivative thereof. Suitable reactive
derivatives include the acid halides and acid anhydrides,
especially the acid anhydrides. Where an acid itself is employed,
we prefer to carry out the reaction in the presence, as catalyst,
of a strong acid, for example a mineral acid such as hydrochloric
acid or sulfuric acid or an organic sulfonic acid such as
p-toluenesulfonic acid.
Otherwise, the nature of the acylating agent employed depends upon
the nature of the acyl group which it is desired to introduce, and
these are defined above as the acyl groups which may be represented
by R.sup.3.
The reaction is preferably effected in the presence of an solvent,
the nature of which is not critical, provided that it has no
adverse effect upon the reaction. Suitable solvents include, for
example: ethers, such as diethyl ether, tetrahydrofuran or dioxane;
aromatic hydrocarbons, such as benzene or toluene; aliphatic
hydrocarbons, such as hexane, cyclohexane or heptane; halogenated
hydrocarbons, especially halogenated aliphatic hydrocarbons, such
as methylene chloride or chloroform; ketones, such as acetone or
methyl ethyl ketone; amides, such as dimethylformamide or
dimethylacetamide; organic bases, such as pyridine or
triethylamine; sulfoxides, such as dimethyl sulfoxide; sulfones,
such as sulfolane; water; and mixtures of any two or more thereof.
There is no particular restriction on the ratio of the compound of
formula (IVH) to the acylating agent, but we generally prefer to
employ an excess, suitably a slight excess, of the acylating agent
or an equimolar amount of the two reagents. In general, we would
employ a molar ratio of acylating agent to compound of formula
(IVH) of from 1:1 to 10:1.
The reaction temperature is not critical and the reaction will take
place over a wide range of temperatures; however, we generally
prefer to carry out the reaction at a temperature of from 0.degree.
C. to 100.degree. C. The time required for the reaction will vary
widely, depending upon many factors, notably the nature of the
reagents and the reaction temperature, but, at a temperature within
the recommended range, a period of from 5 minutes to 20 hours will
normally suffice.
Compounds of the invention in which W represents a hydroxymethylene
group, that is to say compounds of formula (VI): ##STR489## (in
which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7a, n and
Ar are as defined above), can be prepared by reacting a compound of
formula (IV) or (IVH) in which W.sup.2 represents a carbonyl group,
that is to say a compound of formula (VII): ##STR490## (in which
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 R.sup.7a, n and Ar are
as defined above) with a reducing agent, such as sodium borohydride
or K-selectride, preferably sodium borohydride. The resulting
compound of formula (VI) can exist in the following tautomeric
forms: ##STR491## but, for convenience, these are all represented
herein by the single formula (VI).
Reaction of the compound of formula (VII) with the reducing agent
is preferably effected in the presence of a solvent. The nature of
the solvent is not critical, provided that it has no adverse effect
upon the reaction. Suitable solvents include, for example:
alcohols, such as methanol, ethanol, propanol, butanol or ethylene
glycol monomethyl ether; and ethers, such as tetrahydrofuran or
dioxane. There is also no criticality as to the ratio of the
compound of formula (VII) to the reducing agent, although an excess
of the reducing agent is generally preferred. In general, we prefer
to employ a molar ratio of reducing agent to compound of formula
(VII) of from 1:1 to 20:1.
The reaction will take place over a wide range of temperatures and
the particular reaction temperature chosen is not particularly
critical. We generally prefer to carry out the reaction at a
temperature of from 0.degree. C. to 100.degree. C. The time
required for the reaction will vary widely, depending upon many
factors, notably the reaction temperature and the nature of the
reducing agent, but a period of from 1 to 20 hours will normally
suffice.
The resulting compounds of formula (VI) can, if desired, be
converted to the corresponding acyl derivatives of formula (VIII):
##STR492## (in which R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.7a, n and Ar are as defined above, and R.sup.11a represents
any one of the acyl groups included within the definition of
R.sup.11). These compounds can exist in the following tautomeric
forms: ##STR493## but, for convenience, they are all represented
herein by a single formula only.
The nature of the reagents, solvent, proportions of reagents and
reaction conditions such as temperature and reaction time, are as
described above in relation to the acylation of a compound of
formula (IVH) to give the corresponding ester. In view of this,
depending upon the precise reaction conditions, where the compound
of formula (VI) used as starting material is a compound in which
R.sup.3 represents a hydrogen atom, then that hydrogen atom may
simultaneously be replaced by an acyl group to give a compound of
formula (VIII) in which both R.sup.3 and R.sup.11a represent the
same acyl group.
Compounds of the invention in which W and U together form a
carbon-carbon double bond, that is to say compounds of formula
(IX): ##STR494## (in which R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.7a, n and Ar are as defined above) can be prepared
by eliminating water from the above compound of formula (VI) or
eliminating an acid R.sup.11a OH from the aforementioned compound
of formula (VII). The compounds of formula (IX) can exist in
various tautomeric forms, as illustrated below: ##STR495##
Elimination of water or of the acid R.sup.11a OH from the compound
of formula (VI) or (VIII) may be effected by contacting in the
compound with an acid catalyst in a solvent; alternatively, if an
acidic solvent is employed, then no additional acid catalyst is
required.
Suitable acid catalysts include: inorganic acids, such as
hydrochloric acid or sulfuric acid; organic carboxylic acids, such
as acetic acid; and organic sulfonic acids, such as
p-toluenesulfonic acid. The nature of the solvent employed is not
critical, provided that it has no adverse effect upon the reaction.
Suitable solvents include, for example: ethers, such as diethyl
ether, tetrahydrofuran or dixoane; aromatic hydrocarbons, such as
benzene, toluene or xylene; aliphatic hydrocarbons, such as hexane,
cyclohexane or heptane; halogenated hydrocarbons, especially
halogenated aliphatic hydrocarbons, such as methylene chloride or
chloroform; ketones, such as acetone or methyl ethyl ketone; water;
and mixtures of any two or more thereof.
There is no particular restriction on the ratio of the compound of
formula (VI) or (VIII) to the acidic catalyst. However, we
generally prefer to employ a molar ratio of said compound to said
catalyst of from 1:0.001 to 1:1, more preferably from 1:0.01 to
1:0.1.
Where an acidic solvent is to be employed, we prefer to use an
organic acid, particularly an organic carboxylic acid, such as
acetic acid.
The reaction will take place over a wide range of temperatures,
although we generally prefer to employ a temperature of from
0.degree. C. to 100.degree. C. The time required for the reaction
may vary widely, depending upon many factors, notably the nature of
the reagents and the reaction temperature, but a period of from 5
minutes to 20 hours will normally suffice.
Compounds of formula (IX) may also be prepared by hydrolysis of the
corresponding imino compound of formula (X): ##STR496## (in which
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7a, n and Ar are
as defined above; and Y is also as defined above, i.e. it is an
oxygen atom or an imino group).
The compound of formula (X) may be prepared from the compound of
formula (V) by a series of reactions analogous to those employed to
prepare the compound of formula (IX) from the compound of formula
(VII), employing the same reagents and reaction conditions.
The hydrolysis reaction employed is the same as that employed to
convert the compound of formula (V) into the compound of formula
(IV) and may be carried out under the same conditions and employing
the same reagents as described in the context of that reaction. As
with that reaction, the hydrolysis in this reaction may lead to
removal of any acyl group represented by R.sup.3 and its
replacement by a hydrogen atom, to give a compound of formula
(IXH): ##STR497## (in which R.sup.1, R.sup.2, R.sup.4, R.sup.5,
R.sup.7a, n and Ar are as defined above). However, the acyl group
may be kept intact by selecting suitable reaction conditions. Also,
if desired, the acyl group may be reinstated by an acylation
reaction, as described above in relation to acylation of the
compound of formula (IVH).
Compounds of formula (I) in which W represents a methylene group,
that is to say compounds of formula (XI): ##STR498## (in which
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7a, n and Ar are
as defined above), may be prepared by hydrogenation of a compound
of formula (IX).
This hydrogenation is preferably effected in the presence of a
catalyst, for example palladium-on-carbon, Raney nickel or platinum
oxide, of which palladium-on-carbon is preferred. The partial
pressure of hydrogen is preferably from 1 to 100 atmospheres (about
1 to 101 bars), more preferably from 1 to 6 atmospheres (about 1 to
6 bars). The reaction is preferably effected in the presence of a
solvent, the nature of which is not critical, provided that it has
no adverse effect upon the reaction. Suitable solvents include, for
example: alcohols, such as methanol or ethanol; aromatic
hydrocarbons, such as benzene or toluene; ethers, such as
tetrahydrofuran; organic acids, such as acetic acid; amides, such
as dimethylformamide or dimethylacetamide; water; and mixtures of
any two or more thereof. The reaction will take place over a wide
range of temperatures, but we normally find it convenient to carry
out the reaction at a temperature within the range from room
temperature to 50.degree. C. The time required for the reaction
will vary widely, depending upon many factors, notably the nature
of the reagents and the reaction temperature, but a period of from
5 minutes to 20 hours will normally suffice, where a temperature
within the recommended range is employed.
Compounds of formula (I) in which W represents a carbonyl group and
U, R.sup.1 and the carbon atom to which R.sup.1 is attached
together represent a group of formula --CH.dbd.C<, that is to
say a compound of formula (XII): ##STR499## (in which R.sup.2,
R.sup.3 R.sup.4, R.sup.5, R.sup.7a, n and Ar are as defined above),
can be prepared by reacting a compound of formula (XIII):
##STR500## (in which R.sup.2, R.sup.3, R.sup.4, R.sup.5 R.sup.7a,
A, X, n and Ar are as defined above and L and U are as defined
below) with thiourea, to give a compound of formula (XIV):
##STR501## (in which R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7a,
Y, n and Ar are as defined above and L and U are as defined below)
and then hydrolizing this compound in the presence of an acid to
give said compound of formula (XII).
In the above formulae, L represents a group of formula -OR.sup.3,
in which R.sup.3 is as defined above, and U represents a methylene
group; alternatively, U, L and the carbon atom to which the group
represented by l is attached, together form a group of formula
--CH.dbd.C<.
The reactions of the compound of formula (XIII) with thiourea and
the hydrolysis of the compound of formula (XIV) thus produced to
give the desired compound of formula (XII) are similar to the
reactions of the compound of formula (II) with thiourea to give the
compound of formula (V) and the hydrolysis of this to give the
compound of formula (IV) and may be carried out employing the same
reagents and under the same reaction conditions.
Compounds of formulae (X), (IXH), (XI), (XII) and (XIV) exist as
tautomeric forms, analogous to those already described above in
relation to compounds of formulae (IV), (VI), (VIII) and (IX),
although all such tautomers are represented herein by a single
formula only, for convenience.
Compounds of formula (I) in which W represents a group of formula
>C.dbd.N-OR.sup.12a, that is to say compounds of formula (XV):
##STR502## (in which: R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.7a, U, n and Ar are as defined above; and R.sup.12a
represents a hydrogen atom, a C.sub.1 -C.sub.10 alkyl group or a
substituted C.sub.1 -C.sub.10 alkyl group, as defined for
R.sup.12), can be prepared by reacting the corresponding compound
in which W represents a carbonyl group, that is to say a compound
of formula (XVI): ##STR503## (in which R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.7a, U, n and Ar are as defined above) with
a hydroxylamine derivative of formula (XVII):
(in which R.sup.12a is as defined above) or a salt thereof.
The compounds of formulae (XV) and (XVI) can exist in tautomeric
forms, for example as follows in relation to the compound of
formula (XV): ##STR504## however, for convenience, these are
represented herein by a single formula only.
The nature of the hydroxylamine derivative of formula (XVII)
depends upon the nature of the group .dbd.NOR.sup.12a which it is
desired to introduce into the compound. The hydroxylamine
derivative may be employed in the form of a salt thereof, for
example a salt with a mineral acid, such as hydrochloric acid or
sulfuric acid.
The reaction may be effected in the presence of an acid-binding
agent. Where an acid-binding agent is employed, it is preferably an
alkali metal hydroxide (such as potassium hydroxide) or an alkali
metal carbonate (such as sodium carbonate or potassium
carbonate).
The reaction is preferably effected in the presence of a solvent,
the nature of which is not critical, provided that it has no
adverse effect upon the reaction. Examples of suitable solvents
include: alcohols, such as methanol, ethanol, propanol, butanol or
ethylene glycol monomethyl ether; ethers, such as tetrahydrofuran
or dioxane; amides, such as dimethylformamide or dimethylacetamide;
sulfoxides, such as dimethyl sulfoxide; sulfones, such as
sulfolane; organic bases, such as triethylamine or pyridine; water;
and mixtures of any two or more thereof.
There is no particular limitation on the molar ratio of the
hydroxylamine derivative of formula (XVII) to the compound of
formula (XVI) and the reaction will take place at any molar ratio.
However, we generally prefer to employ an excess of the
hydroxylamine derivative, preferably a large excess, with respect
to the compound of formula (XVI). A preferred molar ratio of the
hydroxylamine derivative (XVII) to the compound of formula (XVI) is
from 1:1 to 50:1.
If an acid addition salt of the hydroxylamine derivative (XVII) is
employed, then we prefer to carry out the reaction in the presence
of an acid-binding agent. The amount of acid-binding agent is not
critical and an amount less than equimolar with respect to the salt
of the hydroxylamine derivative can be employed.
The reaction will take place over a wide range of temperatures and
the particular temperature chosen is not critical. We prefer to
carry out the reaction at a temperature within the range from
0.degree. C. to 100.degree. C. The time required for the reaction
will vary widely, depending upon many factors, notably the nature
of the reagents and the reaction temperature, but, at temperatures
within the preferred range given above, a period of from 5 minutes
to 10 days will normally suffice.
Compounds of formula (I) in which W represents a group of formula
>C.dbd.N-O-R.sup.12b (in which R.sup.12b represents any one of
the acyl groups defined for R.sup.12), that is to say compounds of
formula (XVIII): ##STR505## (in which R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.7a, R.sup.12b, U, n and Ar are as defined
above), may be prepared by reacting the corresponding compound of
formula (XV) in which R.sup.12a represents a hydrogen atom, that is
to say a compound of formula (XIX): ##STR506## (in which R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7a, U, n and Ar are as
defined above) with an acylating agent, preferably an acid halide
or acid anhydride, especially an acid anhydride.
The compounds of formula (XVIII) can exist in the form of
tautomers, analogous to those defined above in relation to the
other similar compounds. However, for convenience, these tautomers
are all represented herein by a single formula (XVIII).
The acylation reaction of this compound of formula (XIX) to give
the compound of formula (XVIII) is essentially the same as the
reaction employed to acylate the compound of formula (IVH) and may
be carried out under the same conditions and employing the same
reagents, solvents etc as described heretofore in relation to that
acylation reaction.
The compounds of the invention in which W represents a group of
formula >C.dbd.N-OR.sup.12 (in which R.sup.12 is as defined
above), that is to say the oxime, oxime ether and oxime ester
compounds, i.e. compounds of formulae (XV), (XVIII) and (XIX), can
exist in both the syn and anti forms, and both forms are included
within the scope of the present invention. These oxime, oxime ether
and oxime ester compounds can be converted into their salts by
conventional means. As with the salts described previously, there
is no particular limitation on the nature of the salt, provided
that, where the salt is to be employed for therapeutic purposes, it
should be pharmaceutically acceptable. Suitable salts include:
alkali metal salts, such as the sodium or potassium salt; alkaline
earth metal salts, such as the calcium salt; and salts with
trivalent metals, such as the aluminum salt. However, other salts,
including those other ones described above can also be formed.
Compounds of the invention in which R.sup.6 and/or R.sup.7
represents an alkyl group or substituted alkyl group, i.e.
compounds of formula (XX): ##STR507## (in which R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, W, U, n and Ar are as defined above; and
R.sup.6b and R.sup.7b are the same or different and each represents
a hydrogen atom, a C.sub.1 -C.sub.10 alkyl group or a substituted
C.sub.1 -C.sub.10 alkyl group, as defined in relation to R.sup.6
and R.sup.7, provided that R.sup.6b and R.sup.7b do not both
represent hydrogen atoms), can be prepared by reacting a compound
of formula (XXI): ##STR508## (in which R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.7a, W, U, n and Ar are as defined above)
with an alkyl halide or substituted alkyl halide of formula
(XXII):
(in which R.sup.20 represents R.sup.6b or R.sup.7b and X represents
a halogen atom, for example a fluorine, chlorine, bormine or iodine
atom, preferably a chlorine or bromine atom.
The reaction is preferably effected in the presence of an
acid-binding agent. The purpose of the acid-binding agent is to
remove from the reaction system the hydrogen halide HX produced by
the reaction and any compound capable of doing this may be
employed. Examples of suitable acid-binding agents include: alkali
metal carbonates, such as sodium carbonate or potassium carbonate;
alkali metal hydroxides, such as sodium hydroxide or potassium
hydroxide; alkali metal bicarbonates, such as sodium bicarbonate or
potassium bicarbonate; alkaline earth metal hydroxides, such as
calcium hydroxide; alkali metal hydrides, such as sodium hydride or
potassium hydride; alkali metal alkoxides, such as sodium methoxide
or sodium ethoxide; organic lithium compounds, such as butyllithium
or t-butyllithium; lithium dialkylamides, such as lithium
diisopropylamide or lithium dicyclohexylamide; and organic bases,
such as pyridine or triethylamine. Of these, the alkali metal
carbonates, especially potassium carbonate, are preferred.
The relative proportions of the base and the compound of formula
(XXI) are not particularly critical and may vary over a wide range.
For example, a molar ratio of base to compound (XXI) of from 0.5:1
to 20:1 is preferred, more preferably from 1:1 to 10:1.
The reaction is preferably effected in the presence of a solvent,
the nature of which is not critical, provided that it has no
adverse effect upon the reaction. Suitable solvents include, for
example: ketones, such as acetone or methyl ethyl ketone; ethers,
such as diethyl ether, tetrahydrofuran or dioxane; aromatic
hydrocarbons, such as benzene, toluene or xylene; aliphatic
hydrocarbons, such as hexane, heptane or cyclohexane; amides, such
as dimethylformamide or dimethylacetamide; sulfoxides, such as
dimethyl sulfoxide; sulfones, such as sulfolane; halogenated
hydrocarbons, especially halogenated aliphatic hydrocarbons, such
as methylene chloride, chloroform or (1,2-dichloroethane; organic
bases, such as pyridine or triethylamine; water; and mixtures of
any two or more thereof.
The molar ratio of the compound of formula (XXI) to the alkyl
halide of formula (XXII) is not particularly critical but, in order
to ensure that the reaction goes to completion, we prefer to employ
an excess of the alkyl halide. In general, the molar ratio of the
alkyl halide to the compound of formula (XXI) is from 0.5:1 to
20:1, more preferably from 1;1 to 10:1. Where only a group R.sup.6b
is to be introduced into the compound, a still more preferred molar
ratio is from 1:1 to 5:1, most preferably from 1:1 to 3:1. Where
both groups R.sup.6b and R.sup.7b are to be introduced, the more
preferred ratio is from 1:1 to 10:1 and the most preferred ratio is
from 3:1 to 6:1.
The reaction will take place over a wide range of temperatures and
the particular reaction temperature is not particularly critical.
We generally prefer to carry out the reaction at a temperature of
from -10.degree. C. to +100.degree. C., more preferably from
15.degree. to 40.degree. C. The time required for the reaction may
vary widely, depending upon many factors, notably the reaction
temperature and the nature of the reagents, however, at a
temperature within the preferred range, a period of from 10 minutes
to several days, more commonly from 1 hour to 4 days, will normally
suffice.
Where only R.sup.6b is to be introduced, a preferred reaction
temperature is from 0.degree. to 100.degree. C., more preferably
from 15.degree. to 40.degree. C. At such a temperature, the
reaction time will normally be from 10 minutes to several hours,
commonly from 30 minutes to 3 hours.
Where both R.sup.6b and R.sup.7b are to be introduced, a preferred
reaction temperature is from 0.degree. to 100.degree. C., more
preferably from 15.degree. to 40.degree. C. At such a temperature,
the reaction time will normally be from 10 minutes to several days,
commonly from 5 hours to 2 days.
The reaction normally takes place preferentially at the nitrogen
atom at the 3-position of the thiazolidine ring and, accordingly,
where the quantity of alkyl halide (XXII) is restricted, the
principal product will normally be a compound in which the alkyl or
substituted alkyl group has been introduced at that position. Where
R.sup.7a represents a hydrogen atom in the compound of formula
(XXI), it is possible to replace this by an alkyl or substituted
alkyl group by this reaction and, provided sufficient alkyl halide
(XXII) is employed, disubstitution will take place.
Where a compound in which R.sup.6 and/or R.sup.7 represents a
carboxyalkyl group is required, we prefer to employ a compound of
formula (XXII) in which R.sup.20 represents an alkoxycarbonylalkyl
or substituted alkoxycarbonylalkyl group, to give the corresponding
compound of formula (XX) where R.sup.6b and/or R.sup.7b represents
that alkoxycarbonylalkyl or substituted alkoxycarbonylalkyl group.
The resulting compound of formula (XX) may then be hydrolized to
remove the alkoxy or substituted alkoxy part of this
alkoxycarbonylalkyl group and give a free carboxyalkyl group. In
general, particularly where W is >CH.sub.2 or >C.dbd.O, the
hydrolysis reaction employed is similar to the hydrolysis employed
to convert the compound of formula (V) to a compound of formula
(IV) and may be carried out under the same reaction conditions and
employing the same reagents. In the case of lower alkyl, e.g. ethyl
or t-butyl, esters, the free acid may be formed at a relatively low
temperature, e.g. from 0.degree. to 5.degree. C., by treatment with
an aqueous alkali, e.g. alkali metal hydroxide, such as sodium
hydroxide. In the case of alkoxyalkyl esters, e.g. the
Z-methoxyethyl esters, the reaction is preferably effected at a
higher temperature in the presence of an acid. As with the
previously described hydrolysis reaction, there is a possibility
that the hydrolysis may also hydrolize any acyl group represented
by R.sup.3 in the compound of formula (XX) to give a compound (XXI)
in which R.sup.3 represents a hydrogen atom. However, this may be
avoided by appropriate choice of reagents and reaction
conditions.
Compounds of the invention in which R.sup.3 represents a sulfo
(HSO.sub.3 -) group or an esterified sulfo group of formula
-SO.sub.3 R.sup.8, i.e. compounds of formula (XXIII): ##STR509##
(in which R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, W, U, n and Ar are as defined above), may be prepared by
reacting the corresponding compound of formula (I) in which R.sup.3
represents a hydrogen atom, e.g. a compound of formula (IVH) or
(IXH), with a corresponding halosulfonic acid or halosulfonate of
formula (XXIV):
(in which R.sup.8 and X are as defined above).
The reaction is similar to the reaction to introduce an alkyl or
substituted alkyl group R.sup.6b or R.sup.7b into a compound of
formula (XXI) and may be carried out under the same conditions and
employing the same solvents and acid-binding agents.
In all of the compounds of the invention, the carbon atom at the
5-position of the thiazolidine ring is asymmetric. Moreover, when
R.sup.1 represents an atom of a group (i.e. it does not, together
with U, form a double bond), the carbon atom at the 2-position of
the chroman ring is asymmetric. When W represents a group of
formula >CH-OR.sup.11, then the carbon atom at the 4-position of
the chroman ring is also asymmetric. It will, therefore, be
appreciated that a variety of isomers of the compounds of the
invention are possible, as a result of different configurations of
substituent groups about these asymmetric carbon atoms. Although
all such isomers are represented herein by a single formula only,
the present invention envisages both the individual isolated
isomers and mixtures thereof. The compounds of the invention may be
produced in the form of individual isomers by using an isolated
isomer as the starting material or by stereospecific synthesis
techniques. Alternatively, the compounds may be produced as a
mixture of such isomers, in which case they may be employed in the
form of such a mixture or the individual isomers may be separated
by conventional resolution techniques.
The compounds of the invention obtained by any of the reactions
discussed above may be isolated and purified by conventional
techniques, including any one or more of the following:
concentration; evaporation of solvent under reduced pressure;
extraction with a solvent; crystallization and recrystallization;
solvent transfer; chromatography techniques, especially column
chromatography and thin layer chromatography; and optical
resolution.
The .alpha.-halocarboxylic acid derivatives of formula (II)
employed as starting materials in the processes of the present
invention can be prepared by a variety of methods, for example as
follows.
Method A
Method A is the method described in more detail in copending U.S.
patent application Ser. No. 644,996 and prepares compounds where W
and U both represent methylene groups, that is to say compounds of
formula (XXX), as illustrated in the following reaction scheme:
##STR510##
In the above formulae, R.sup.1 -R.sup.5, R.sup.7a, Ar, n, A and X
are as defined above, n'=(n-1); and R.sup.30 represents a
hydroxy-protecting group.
Step A1
The chroman carboxylic acid homologs (XXXI), which are the starting
materials for this Method, may be prepared as described, for
example, in the Journal of the American Oil Chemists Society, 51,
200 (1974).
These acids (XXXI) are reduced with a reducing agent, such as
lithium aluminum hydride or Vitride [sodium
bis(2-methoxyethoxy)aluminum hydride], to give the corresponding
chroman alcohol homolog (XXXII). This reaction is preferably
effected in the presence of a solvent, the nature of which is not
critical, provided that it does not interfere with the reaction.
Suitable solvents include: ethers, such as diethyl ether,
tetrahydrofuran or ethylene glycol dimethyl ether; aromatic
hydrocarbons, such as benzene, toluene or xylene; and aliphatic
hydrocarbons, such as hexane, heptane, cyclohexane, petroleum
ether, ligroin or ethylcyclohexane.
The ratio of the amount of acid (XXXI) to reducing agent is not
particularly critical, but we generally prefer to use a slight
molar excess of reducing agent. Preferably the amount of reducing
agent is from 1 to 2 moles per mole of acid (XXXI). The reaction
conditions, particularly the reaction temperature and time, will
vary depending upon many factors, such as the nature of the
starting material, the reducing agent and the solvent, but the
reaction is generally carried out at a temperature of from
0.degree. to 100.degree. C. At such a temperature, a reaction
period of from 10 minutes to 20 hours will normally suffice.
Alternatively, the chroman alcohol homolog (XXXII) may be prepared
by reacting a hydroquinone with a compound of formula (XXXV):
##STR511## (in which n and R.sup.1 are as defined above),
especially the compound of formula (XXXV) where R.sup.1 represents
a methyl group, in the presence of aluminum chloride, as described
in West German Patent No. 3,010,504.
Step A2
The chroman alcohol homologs of formula (XXXII) obtained in Step A1
may be converted to the corresponding nitrophenoxyalkyl chroman
compounds (XXXIII). However, before carrying out this reaction, we
prefer that the phenolic hydroxy group should be protected by a
hydroxy-protecting group R.sup.30.
The nature of the hydroxy-protecting group is not critical and any
such group commonly used in this type of reaction and compound may
be employed. Suitable groups include: alkoxyalkyl groups, such as
the methoxymethyl group; alkoxycarbonylalkyl groups, such as the
ethoxycarbonylmethyl, t-butoxycarbonylmethyl,
1-methoxycarbonyl-1-methylethyl and
1-(t-butoxycarbonyl)-1-methylethyl groups; aralkyl groups, such as
the benzyl group; the 2-tetrahydropyranyl group; and acyl groups,
such as the acetyl or benzoyl groups. The alkoxyalkyl,
alkoxycarbonylalkyl and 2-tetrahydropyranyl groups are preferred.
The reaction is normally effected by contacting a compound R.sup.30
X (in which R.sup.30 is as defined above and X represents a halogen
atom, preferably a chlorine atom), such as methoxymethyl chloride,
ethoxycarbonylmethyl bromide, 1-(t-butoxycarbonyl)-1-methylethyl
bromide, benzoyl chloride or benzyl chloride, more preferably
methoxymethyl chloride or benzoyl chloride, with the compound of
formula (XXXII) in the presence of a base such as an alkali metal
or alkaline earth metal hydride (e.g. sodium hydride or calcium
hydride) or an alkali metal alkoxide (e.g. sodium methoxide, sodium
ethoxide or potassium t-butoxide). The reaction is normally carried
out in the presence of a solvent, for example: an ether, such as
diethyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon,
such as benzene, toluene or xylene; an aliphatic hydrocarbon, such
as hexane or heptane; an amide, such as dimethylformamide or
dimethylacetamide; a sulfoxide, such as dimethyl sulfoxide; or a
sulfone, such as sulfolane. There is no particular limitation on
the molar ratio of compound (XXXII) to the compound R.sup.30 X. In
general, we prefer to employ from about 0.8 to 1.2 mole of the
compound R.sup.30 X per mole of the compound (XXXII). The reaction
conditions, particularly the reaction temperature and time, may
vary depending upon a number of factors, especially the natures of
the starting material, the compound R.sup.30 X and the solvent, but
we normally prefer a reaction temperature of from 0.degree. to 50
.degree. C. and a time of from several minutes to several tens of
minutes.
The protection chroman alcohol produced by this reaction can, if
desired, be isolated and purified, but it may be, and preferably
is, converted to the nitrophenoxyalkylchroman compound of formula
(XXXIII) without intermediate isolation.
Conversion to the compound of formula (XXXIII) is effected by
reacting the protected compound (XXXII) with a halonitroaryl
compound, e.g. a 4- or 3-halonitrobenzene, of formula
X-(AR)-NO.sub.2 (in which X and Ar are as defined above) in the
presence of a base, such as sodium hydride, in a solvent, such as
dimethyl sulfoxide or dimethylformamide. The amount of
halonitroaryl compound employed is preferably about 2 moles per
mole of protected compound (XXXII). The reaction temperature is
preferably from 30.degree. to 100.degree. C. and the time required
for the reaction is usually from several minutes to several
hours.
Sept A3
The nitro compound of formula (XXXIII) thus obtained is reduced in
this step to the corresponding amino compound of formula (XXXIV).
In the course of or before or after this reduction, the protecting
groups R.sup.30 may be allowed to remain as it is, removed or
converted to another group (particularly an acyl group, such as an
acetyl or benzoyl group).
When deprotection of the compound (XXXIII) is desired, this can
easily be achieved by reacting the compound (XXXIII) with a dilute
aqueous acid (such as hydrochloric acid, sulfuric acid or nitric
acid) to hydrolyse the protecting group. The reaction is normally
carried out in the presence of a solvent, for example: an alcohol,
such as methanol, ethanol or propanol; an ether, such as
tetrahydrofuran or dioxane; a ketone, such as acetone or methyl
ethyl ketone; an organic acid, such as acetic acid or propionic
acid; dimethyl sulfoxide; dimethylformamide; or water. Of these,
water or an organic acid is preferred. The amount of acid used for
hydrolysis is preferably from 0.01 to 5 moles, more preferably from
0.01 to 1 mole, per mole of the compound (XXXIII). We prefer to
carry out the reaction in the presence of a large molar excess of
water or of acetic acid as the solvent. The reaction temperature is
preferably from ambient temperature to 100.degree. C. and the time
required for the reaction is normally from several minutes to about
20 hours.
If it is desired to convert the protecting group R.sup.30 to
another group, particularly an acyl group, this may be achieved by
acylation of the deprotected compound obtained as described above.
The acylating agent may be an acid halide, such as acetyl chloride
or benzoyl chloride, or an acid anhydride, such as acetic
anhydride. This reaction is preferably carried out in the presence
of an organic amine (such as pyridine or triethylamine) or in the
presence of an inorganic base (for example an alkali metal
hydroxide, such as sodium hydroxide or potassium hydroxide, or an
alkali metal carbonate or bicarbonate, such as sodium carbonate,
potassium carbonate or sodium bicarbonate). The acylating reaction
is preferably carried out in the presence of a solvent, for
example: an aliphatic hydrocarbon, such as hexane, cyclohexane,
heptane, ligroin or ethylcyclohexane; an aromatic hydrocarbon, such
as benzene, toluene or xylene; an organic amine, such as pyridine
or triethylamine; a ketone, such as acetone or methyl ethyl ketone;
an amide, such as dimethylformamide; a sulfoxide, such as dimethyl
sulfoxide; or water. The ratio of the amount of deprotected
compound (XXXIII) to acylating agent is not particularly critical,
however, a slight molar excess of acylating agent is usually
preferred, for example from 1 to 1.5 moles of acylating agent per
mole of deprotected compound (XXXIII). Where an organic amine is
employed as the acid-binding agent, it may be employed in any
amount from 1 mole to a large molar excess per mole of the compound
of formula (XXXIII). Where an inorganic base is employed as the
acid-binding agent, it is preferably employed in an amount of from
1 to 10 moles per mole of the compound of formula (XXXIII). The
reaction conditions, particularly the reaction temperature and
time, may vary depending upon a number of factors, particularly the
natures of the starting material and solvent employed, but the
reaction is preferably effected at a temperature of from 0.degree.
to 100.degree. C. for a period of from several minutes to 20
hours.
The nitro compound of formula (XXXIII) (which may optionally have
been subjected to any of the processes described above) is then
reduced to the amino compound of formula (XXXIV). The reduction may
be a catalytic reduction process employing hydrogen, or reduction
with a metal (Such as zinc or iron) and an acid (which may be a
mineral acid such as hydrochloric acid or sulfuric acid or an
organic acid such as acetic acid). Preferably a catalytic reduction
process is employed. The catalyst employed for this catalytic
reduction is preferably palladium-on-carbon, Raney nickel or
platinum oxide, of which palladium-on-carbon is particularly
preferred. The hydrogen pressure is preferably from 1 to 100
atmospheres (about 1 to 101 bars), more preferably from 1 to 6
atmospheres (about 1 to 6 bars). The reaction is preferably
effected in the presence of a solvent, the nature of which is not
critical, provided that it has no adverse effect upon the reaction.
Suitable solvents include: alcohols, such as methanol or ethanol;
aromatic hydrocarbons, such as benzene or toluene; ethers, such as
tetrahydrofuran; organic acids, such as acetic acid; water; or
mixtures of any two or more thereof. The reaction conditions,
particularly the reaction temperature and time, may vary depending
upon a number of factors, particularly the nature of the starting
material, the method employed for reduction and the solvent, but
the reaction is normally effected at a temperature from ambient
temperature to 50.degree. C. and the period required for the
reaction is generally from several minutes to about 20 hours.
Step A4
The chroman derivative of formula (XXXIV), prepared as described in
step A3 above, is diazotized and then subjected to a Meerwein
arylation, to give the desired .alpha.-halocarboxylic acid compound
of formula (XXX). The two reactions are preferably effected
sequentially in the same reaction system.
The diazotization reaction comprises reacting the amino compound of
formula (XXXIV) with a nitrite (such as sodium nitrite) in the
presence of an acid, such as hydrochloric acid or hydrobromic
acid.
The Meerwein arylation reaction comprises reacting the resulting
diazonium compound with an acrylic compound of formula CH.sub.2
.dbd.CR.sup.7a A (in which R.sup.7a and A are as defined above),
e.g. acrylic acid, an acrylic or methacrylic acid ester (such as
methyl acrylate, ethyl acrylate or ethyl methacrylate) or another
acrylic acid derivative (such as acrylonitrile, acrylamide,
methacrylonitrile or methacrylamide), in the presence of a
catalytic amount of a cuprous compound (which may be a salt, such
as cuprous chloride, or another cuprous compound such as cuprous
oxide). The acrylic and methacrylic acid esters are preferred and
the preferred cuprous compound is cuprous oxide.
The reactions are preferably effected in the presence of a solvent,
the nature of which is not critical, provided that it does not
interfere with the reactions. Suitable solvents include: alcohols,
such as methanol or ethanol; ketones, such as acetone or methyl
ethyl ketone; water; or a mixture of any two or more thereof. The
molar ratio of the amino compound of formula (XXXIV) to the acrylic
acid or derivative thereof of formula CH.sub.2 .dbd.CR.sup.7a A is
preferably from 1:1 to 1:15, more preferably from 1:5 to 1:10. The
molar ratio of the amino compound (XXXIV) to the cuprous compound
is preferably from 1:0.01 to 1:1, more preferably from 1:0.03 to
1:0.3. The reaction conditions, particularly the reaction
temperature and time, may vary depending upon a number of factors,
especially the natures of the starting materials and the solvent
employed, but the reaction is normally carried out at a temperature
from ambient temperature to 100.degree. C., preferably from
30.degree. to 60.degree. C., and the period required for the
reaction is normally from about 20 minutes to about 20 hours, more
preferably from 30 minutes to 2 hours.
Method B
This method may also be used to prepare compounds of formula (II)
in which both W and U represent methylene groups and is especially
useful for preparing compounds in which n is 2. The reactions
involved are illustrated in the following reaction scheme:
##STR512##
In the above reaction scheme, R.sup.1 -R.sup.5 are as defined
above, R.sup.31 represents an alkyl group and Me represents the
methyl group.
In this reaction, the chroman alcohol of formula (XXXIIa) or its
analogs in which n is an integer other than 2, may be prepared from
the hydroquinone derivative of formula (XXXVI) via the sequence of
steps indicated as steps B1, to give the compound of formula
(XXXVIII), followed by step B2, and then step B3 (analogous to step
A1 1 of Method A), according to the method described in the Journal
of the American Oil Chemists Society, 51, 200 (1974).
Alternatively, it can be synthesized in a single step by reacting
the hydroquinone derivative (XXXVI) with the dihydropyran
derivative of formula (XXXVII), as illustrated in step B4 by the
method described in Japanese Patent Application Kokai No.
201775/83. Subsequently, the resulting compound of formula (XXXIIa)
may be subjected to steps A2, A3 and A4, to give the desired
compound of formula (XXX).
Method C
This method is also useful for synthesizing compounds of formula
(II) in which both W and U represent methylene groups. This method
may be carried out as illustrated by the following reaction scheme:
##STR513##
In the above formulae, R.sup.2, R.sup.4, R.sup.5 and R.sup.30 are
as defined above; R.sup.1a represents any one of the groups
heretofore defined for R.sup.1, other than the hydrogen atom; and
R.sup.32 represents a hydrogen atom or a carboxy-protecting group,
preferably an alkyl, alkenyl, alkynyl, aralkyl or optionally
substituted phenyl group, more preferably a C.sub.1 -C.sub.4 alkyl
group.
Steps C1-C4
These steps are carried out essentially as described in the Journal
of Medicinal Chemistry, 18, 934 (1975).
Step C5
In this step, the phenolic hydroxy group is, if required,
protected. We prefer that this hydroxy group should be protected
prior to step C6. Examples of protecting groups R.sup.30 have been
given above in relation to Method A and the method of introducing
the protecting group is also as described above in relation to step
A2. However, in this step, we prefer to employ the compound
R.sup.30 X in excess, preferably a molar ratio of the compound
R.sup.30 X to the compound of formula (XLIII) of from 1:1 to 2:1.
The reaction is preferably effected at a temperature of from
0.degree. to 50.degree. C., more preferably from 10.degree. to
25.degree. C. The time required for the reaction will vary,
depending upon many factors, but a period of from several minutes
to several hours will normally suffice. The resulting compound of
formula (XLIV) may then be used in step C6 without intermediate
isolation.
Step C6
In this step, a chromancarboxylic acid derivative of formula (XLV)
having a protected hydroxy group at the 6-position and a group
R.sup.1a at the 2-position is prepared. This may be achieved by
reacting the compound of formula (XLIV) with a base in an inert
solvent in order to generate a carbanion and then reacting this
carbanion with a compound of formula R.sup.1a X.sup.1 (in which
R.sup.1a is as defined above and X.sup.1 represents a halogen atom,
for example a chlorine, bromine or iodine atom, or a sulfonyloxy
group, for example a methanesulfonyloxy, ethanesulfonyloxy,
benzenesulfonyloxy or p-toluenesulfonyloxy group).
Any base may be employed in the reaction to generate the carbanion,
and examples of such bases include: organic lithium compounds, such
as methyllithium, butyllithium, t-butyllithium or phenyllithium;
lithium dialkylamides, such as lithium diisopropylamide, lithium
dicyclohexylamide or lithium N-isopropyl-N-cyclohexylamide; and
alkali metal hydrides, such as lithium hydride, sodium hydride or
potassium hydride. Of these, we prefer the organic lithium
compounds and lithium dialkylamides.
The reaction is preferably effected in the presence of a solvent,
the nature of which is not critical, provided that it has no
adverse effect upon the reaction. Suitable solvents include, for
example, ethers, such as diethyl ether, tetrahydrofuran or
dioxane.
The reaction temperature employed for generation of the carbanion
is preferably relatively low, e.g. from -78.degree. C. to room
temperature. The temperature employed for reaction of this anion
with the compound of formula R.sup.1a X.sup.1 is preferably
somewhat higher, e.g. from 0.degree. C. to 60.degree. C. The time
required for these reactions will vary widely, depending upon many
factors, notably the nature of the reagents and the reaction
temperature, but a period of from 30 minutes to 2 hours will
normally suffice for generation of the carbanion, whilst a period
of from 1 to 24 hours will normally suffice for the subsequent
reaction with the compound R.sup.1a X.sup.1.
Thereafter, the resulting compound of formula (XLV) may be
subjected to the same reactions as described in Method A, to give
the resulting compound of formula (XXX).
If desired, Step C6 may be omitted, to prepare a compound in which
R.sup.1 is a hydrogen atom.
Method D
This method is also described in copending U.S. patent application
Ser. No. 644,996 and prepares compounds of formula (II) in which U
represents a methylene group and W represents a carbonyl group,
that is to say compounds of formula (LI), by the reactions
summarized in the following reaction scheme: ##STR514##
In the above formulae, R.sup.1 -R.sup.5, R.sup.7a, Ar, n, A and X
are as defined above. The reaction sequence comprises the following
steps:
Step D1
The acetophenone derivative of formula (XLVII) which is one of the
starting materials for this step may be prepared, for example, as
described in Chem. Berichte, 95, 1413. The other starting material,
the nitroaryloxyalkyl alkyl ketone of formula (XLVIII), may be
prepared, for example, as described in J. Med. Chem., 21, 386
(1978) and J. Am. Chem. Soc., 99, 7653 (1977).
In this step, the compounds (XLVII) and (XLVIII) are reacted
together in the presence of a secondary amine, as described, for
example, in Japanese Patent Application Kokai No. 19670/77.
The reaction is preferably effected in the presence of a solvent,
the nature of which is not critical, provided that it has no
adverse effect upon the reaction. Suitable solvents include:
aliphatic and aromatic hydrocarbons, such as petroleum ether,
benzene, toluene, xylene, hexane and cyclohexane; halogenated
aliphatic and aromatic hydrocarbons, such as carbon tetrachloride,
methylene chloride, chloroform, chlorobenzene and dichlorobenzene;
ethers, such as diethyl ether, tetrahydrofuran and dioxane; amides,
such as dimethylformamide, dimethylacetamide and
N-methylpyrrolidone; alcohols, such as methanol, ethanol and
ethylene glycol monomethyl ether; esters, such as ethyl acetate;
nitriles, such as acetonitrile; and sulfoxides, such as dimethyl
sulfoxide.
The secondary amine employed in this reaction is preferably a
compound of formula R.sup.a -NH-R.sup.b, in which R.sup.a and
R.sup.b may be the same or different and each represents an alkyl
group, or R.sup.a and R.sup.b, together with the nitrogen atom to
which they are attached, represent a nitrogen-containing
heterocyclic ring system. Examples of such secondary amines include
diethylamine, dimethylamine, N-methylpiperazine, pyrrolidine,
piperidine or morpholine, of which pyrrolidine is particularly
preferred.
The molar ratio of the compound of formula (XLVII) to the compound
of formula (XLVIII) is not particularly critical, but, to avoid
waste, roughly equimolar amounts of the two compounds are used. In
general, the amount of secondary amine is preferably from 0.05 to
1.5 moles, more preferably from 0.1 to 1 mole, per mole of the
compound of formula (XLVII) or (XLVIII).
The reaction conditions particularly reaction temperature and time,
may vary depending upon a number of factors, especially the nature
of the staring materials and of the solvent, but, in general, we
prefer to carry out the reaction at a temperature of from
-30.degree. C. to +150.degree. C., more preferably from 10.degree.
to 120.degree. C., for a period of from 30 minutes to 3 days.
Step D2
In this step, the nitro compound of formula (XLIX) prepared as in
step D1 is reduced t the corresponding amino compound of formula
(L). This reaction is precisely the same as step A3 of Method A,
employing the same reaction conditions and reagents.
Step D3
In this step, the amino compound of formula (L), obtained as
described in step D2, is diazotized and then subjected to a
Meerwein arylation, to give the desired .alpha.-halocarboxylic acid
derivative of formula (LI). These reactions are precisely the same
as those described in step A4 of Method A and may be carried out
employing the same reagents and reaction conditions.
Method E
This method may be used for preparing compounds of formula (II) in
which W represents a carbonyl group and U represents a methylene
group, and where there is a group R.sup.1a (as defined above) at
the 2-position of the chroman ring. The reactions involved are
summarized in the following reaction scheme: ##STR515##
In the above formulae, R.sup.1a, R.sup.2, R.sup.4, R.sup.5,
R.sup.30, R.sup.32 and Ar are as defined above. R.sup.33 represents
a carbonyl-protecting group, examples of which are described in
more detail below.
Step E1
In this step, the starting material of formula (XLII), which may
have been prepared as described in step C3 of Method C, is
subjected to reduction, but under milder conditions than employed
in step C4, so that only the double bond between the 2- and
3-positions is hydrogenated.
The reaction is preferably effected by catalytic hydrogenation.
Suitable catalysts include palladium-on-carbon, Raney nickel and
platinum oxide, of which palladium-on-carbon is preferred. The
reaction is preferably effected employing a partial pressure of
hydrogen of from 1 to 100 atmospheres (about 1 to 101 bars), more
preferably from 1 to 6 atmospheres (about 1 to 6 bars). The
reaction is preferably effected in the presence of a solvent, the
nature of which is not critical, provided that it has no adverse
effect upon the reaction. Suitable solvents include, for example:
alcohols, such as methanol or ethanol; aromatic hydrocarbons, such
as benzene or toluene; ethers, such as tetrahydrofuran; amides,
such as dimethylformamide or dimethylacetamide; organic carboxylic
acids, such as acetic acid; water; and mixtures of any two or more
thereof.
The reaction will take place over a wide range of temperatures, but
we prefer to employ a temperature of from room temperature to
50.degree. C., more preferably from room temperature to 40.degree.
C. The time required for the reaction will vary widely, depending
upon many factors, notably the nature of the reagents and the
reaction temperature; however, at a temperature within the
preferred range described above, the reaction will normally be
complete within a period of from several minutes to several days,
commonly from 30 minutes to 20 hours.
Step E2
In this step, the carbonyl group at the 4-position of the chroman
compound of formula (LII) prepared in step E1 is protected; it is
desirable that this protection should be carried out prior to the
alkylation reaction of step E4.
There is no particular limitation on the nature of the protecting
group employed and any such group commonly used for protecting
carbonyl groups may equally well be used in the present invention.
For example, the oxo compound may be converted into a protected
enol compound, such as an enol ether or enol ester. Alternatively,
it may be converted into a ketone acetal having cyclic or
non-cyclic side chains or into a ketone dithioacetal. Conversion
into a ketone dithioacetal is preferred.
Preferably, R.sup.33 represents a group of formula -B.sup.1
-B.sup.2 -B.sup.1 -, where B.sup.1 represents an oxygen or sulfur
atom (preferably a sulfur atom) and B.sup.2 represents a group of
formula --(CH.sub.2).sub.2 -, --(CH.sub.2).sub.3 --,
--(CH.sub.2).sub.4 -- or --CH.sub.2 --CH.dbd.CH--CH.sub.2 -(cis),
preferably --(CH.sub.2).sub.2 -- or --(CH.sub.2).sub.3 -- and more
preferably --(CH.sub.2).sub.3 --. Such a protected compound may be
prepared by reacting the compound of formula (LII) with a compound
of formula H-B.sup.1 -B.sup.2 -B.sup.1 -H (in which B.sup.1 and
B.sup.2 are as defined above), for example ethylene glycol,
1,3-propanediol, 1,2-ethanedithiol, 1,3-propanedithiol or
cis-2-butene-1,4-diol, preferably 1,3-propanedithiol, under
dehydrating conditions. The reaction may take place in the presence
or absence of a catalyst. Where a catalyst is employed, suitable
catalysts include, for example: Lewis acids, such as boron
trifluoride and diethyl ether and acetic acid complexes thereof, or
aluminum chloride; inorganic acids, such as hydrogen chloride or
sulfuric acid; organic carboxylic acids, such as acetic acid,
tartaric acid, fumaric acid or maleic acid; and organic sulfonic
acids, such as p-toluenesulfonic acid or methanesulfonic acid. We
prefer to use a Lewis acid, more preferably a boron trifluoride
acetic acid complex salt.
The reaction does not always require a solvent; however, if a
solvent is employed, its nature is not critical, provided that it
has no adverse effect upon the reaction. Examples of suitable
solvents include: aromatic hydrocarbons, such as benzene or xylene;
and halogenated hydrocarbons, especially halogenated aliphatic
hydrocarbons, such as chloroform or methylene chloride. Of these,
we prefer halogenated hydrocarbons, such as chloroform.
There is no particular limitation on the proportions of the
compound of formula (LII) to the compound of formula H-B.sup.1
-B.sup.2 -B.sup.1 -H; however, a small excess of H-B.sup.1 -B.sup.2
-B.sup.1 -H is preferred, preferably a molar ratio of the compound
H-B.sup.1 -B.sup.2 -B.sup.1 -H to the compound of formula (LII) of
from 1:1 to 2:1. Equally, there is no particular limitation on the
proportions of catalyst employed. However, a molar ratio of
catalyst to compound of formula (LII) of from 1:1 to 1:4 is
preferred.
The reaction will take place over a wide range of temperatures, but
we generally prefer to carry out the reaction at a temperature of
from 0.degree. to 100.degree. C., more preferably from 10.degree.
C. to 40.degree. C. The time required for the reaction may vary
widely, depending upon the nature of the reagents and the reaction
temperature, but a period of from several minutes to several days,
more commonly from 1 hour to 30 hours, will normally suffice.
Step E3
In this step, the phenolic hydroxy group at the 6-position of the
chroman ring is protected, typically by reaction with a compound of
formula R.sup.30 X (in which R.sup.30 and X are as defined above).
This reaction is similar to the reactions described in steps A2 and
C5 and is preferably carried out employing the same reagents and
under the reaction conditions described in relation to step C5. The
resulting compound of formula (LIV) may be isolated from the
reaction mixture or may be used without intermediate isolation
directly in step E4.
Step E4
In this step, the compound of formula (LIV) is converted to a
carbanion and then reacted with a compound of formula R.sup.1a
X.sup.1 (in which R.sup.1a and X.sup.1 are as defined above). This
reaction is similar to that described above in relation to step C6
and may be carried out employing the same reagents and under the
same reaction conditions as employed in step C6.
If it is desired to prepare a compound in which R.sup.1 represents
a hydrogen atom, step E4 may be omitted, and the product of step
E3--the compound of formula (LIV)--may be employed directly in step
E5.
Step E5
In this step, the chroman-2-carboxylic acid derivative of formula
(LV) is reduced to the corresponding alcohol of formula (LVI). This
reaction is essentially the same as that described above in step A1
of the Method A and may be carried out under the same conditions
and employing the same reagents. However, in this case, we prefer
to employ a temperature within the range from -50.degree. C. to
+120.degree. C.
Step E6
In this step, a group of formula -(Ar)-NO.sub.2 (Ar being as
defined above) is introduced into the compound of formula (LVI)
prepared as described in step E5. This reaction may be effected by
reacting the compound of formula (LVI) with a base to convert it to
the corresponding alkoxide, and then reacting this with a compound
of formula X-(Ar)-NO.sub.2 (in which X and Ar are as defined
above).
Any base capable of forming an alkoxide with the compound of
formula (LVI) may be employed. Examples include: alkali metal and
alkaline earth metal hydrides, such as sodium hydride or calcium
hydride; and alkali metal alkoxides, such as sodium methoxide,
sodium ethoxide or potassium t-butoxide. Of these, we prefer sodium
hydride or sodium ethoxide. The proportions of the compound of
formula (LVI) and the base are not particularly critical; however,
we prefer to employ a slight excess of the base, preferably a molar
ratio of base to compound of formula (LVI) of from 1:1 to 2:1.
The reactions are preferably effected in the presence of a solvent,
the nature of which is not critical, provided that it has no
adverse effect upon the reaction. Suitable solvents include, for
example: ethers, such as diethyl ether, tetrahydrofuran or dioxane;
aromatic hydrocarbons, such as benzene, toluene or xylene;
aliphatic hydrocarbons, such as hexane or heptane; amides, such as
dimethylformamide or dimethylacetamide; sulfoxides, such as
dimethyl sulfoxide; and sulfones, such as sulfolane. Of these, the
amides are preferred. The relative proportions of the compound of
formula X-(Ar)-NO.sub.2 to the compound of formula (LVI) are not
particularly critical to the present invention, however, we prefer
to employ a slight excess of the compound of formula
X-(Ar)-NO.sub.2, preferably a molar ratio of said compound of
formula X-(Ar)-NO.sub.2 to compound of formula (LVI) of from 1:1 to
10:1.
The reaction will take place over a wide range of temperatures, but
we generally prefer to employ a temperature of from 30.degree. C.
to 100.degree. C. The time required for the reaction may vary
widely, depending upon many factors, notably the nature of the
reagents and the reaction temperature. A period of from several
minutes to several hours will normally suffice.
The nitro compound of formula (LVII) thus obtained may then be
converted to the desired compound of formula (XXX) by following
steps A3 and A4 as described in Method A. At some stage in the
course of this, the protected carbonyl group at the 4-position of
the chroman system is deprotected and this may be carried out as
described hereafter in Step E7.
Step E7
In this step, the protected carbonyl group is deprotected. Any
conventional reaction employed to deprotect a protected carbonyl
group may be employed in this step. For example, the protected
compound may be reacted with: a protonic acid, such as hydrochloric
acid or sulfuric acid; a Lewis acid, such as boron trifluoride or
an ether, e.g. diethyl ether, or acetic acid complex thereof, or
aluminum chloride; when B.sup.1 represents a sulfur atom, a heavy
metal salt, heavy metal oxide, heavy metal peroxide or a mixture of
any two or three of these, for example a silver, cadmium,
mercurous, mercuric, cuprous or thallic chloride, bromide, iodide,
nitrate, perchlorate, oxide or peroxide; iodine; a sulfuryl halide,
such as sulfuryl chloride; or an N-haloimide, such as
N-chlorosuccinimide or N-bromosuccinimide. Of these, we prefer
mercuric chloride, mercuric oxide or a mixture thereof, more
preferably a mixture of mercuric chloride and mercuric oxide.
The reaction is preferably effected in the presence of a solvent,
the nature of which is not critical, provided that it has no
adverse effect upon the reaction. Suitable solvents include, for
example: alcohols, such as methanol, ethanol, propanol or
isopropanol; ketones, such as acetone or methyl ethyl ketone;
halogenated hydrocarbons, especially halogenated aliphatic
hydrocarbons, such as chloroform, methylene chloride or
1,2-dichloroethane; ethers, such as tetrahydrofuran or dioxane;
organic carboxylic acids, such as acetic acid; nitriles, such as
acetonitrile; water; and mixtures of any two or more thereof.
The proportions of the compound of formula (LVII) or other
protected compound to the deprotecting agent are not critical.
However, we prefer to employ a slight excess of the deprotecting
agent, e.g. a molar ratio of deprotecting agent to compound of
formula (LII) or other protected compound of from 1:1 to 10:1, more
preferably from 1:1 to 4:1.
The reaction will take place over a wide range of temperatures, but
we generally find it convenient to carry out the reaction at a
temperature within the range from room temperature to 100.degree.
C., more preferably from 40.degree. C. to 80.degree. C. The time
required for the reaction will vary, depending upon many factors,
notably the nature of the reagents and the reaction temperature;
however, at a temperature within the ranges mentioned above, a
period of from several minutes to several hours, more commonly from
30 minutes to 4 hours, will normally suffice.
Thereafter, the compound of formula (LVIII) may be subjected to
steps A3 and A4 to give the desired compound of formula (XXX).
Alternatively, the deprotection step E7 may take place after or
between these steps A3 and A4.
Method F
A particularly preferred process for preparing compounds of formula
(II) in which both W and U represent methylene groups is
illustrated in the following reaction scheme: ##STR516##
In the above formulae, R.sup.1 -R.sup.5 n and Ar are as defined
above and R.sup.11a represents any one of the acyl groups defined
above in relation to R.sup.11.
STEP F1
In this step, a 4-oxochroman derivative of formula (XLIX), which
may have been prepared by a variety of the methods described above,
including, for example step E7 of Method E or step D1 of Method D,
is reduced to the corresponding 4-hydroxy compound of formula
(LIX). Any reducing agent capable of reducing an oxo group on a
saturated ring system to a hydroxy group may be employed. We
generally prefer to employ sodium borohydride or K-selectride, of
which sodium borohydride is particularly preferred.
The reaction is preferably effected in the presence of a solvent,
the nature of which is not critical, provided that it has no
adverse effect upon the reaction. Suitable solvents include, for
example: alcohols, such as methanol, ethanol, propanol, butanol or
ethylene glycol monomethyl ether; and ethers, such as
tetrahydrofuran or dioxane.
There is no particular limitation on the relative proportions of
the compound of formula (XLIX) to the reducing agent, e.g. sodium
borohydride, but we generally prefer to employ an excess,
preferably a slight excess, of the reducing agent. In general, we
would use a molar ratio of reducing agent to compound of formula
(XLIX) of from 1:1 to 20:1.
The reaction will take place over a wide range of temperatures and
the exact temperature chosen is not particularly critical. A
temperature within the range from 0.degree. C. to 100.degree. C. is
generally preferred. The time required for the reaction may vary
widely, depending upon many factors, notably the nature of the
reagents and the reaction temperature. However, a period of from 1
to 20 hours will normally suffice.
Step F2
In this optional step, the compound of formula (LIX) prepared as
described in step F1 is acylated. The acylating agent employed is
preferably an acid halide or acid anhydride.
The reaction is preferably carried out in the presence of a
solvent, the nature of which is not critical, provided that it does
not interfere with the reaction. Suitable solvents include, for
example: ethers, such as diethyl ether, tetrahydrofuran or dioxane;
aromatic hydrocarbons, such as benzene, toluene or xylene;
aliphatic hydrocarbons, such as hexane, cyclohexane or heptane;
halogenated hydrocarbons, especially halogenated aliphatic
hydrocarbons, such as methylene chloride or chloroform; organic
bases, such as pyridine or triethylamine; amides, such as
dimethylformamide or dimethylacetamide; sulfoxides, such as
dimethyl sulfoxide; and sulfones, such as sulfolane.
There is no particular limitation on the proportions of compound of
formula (LIX) to the acylating agent, but we generally prefer to
use equimolar amounts or a slight excess of acylating agent. In
general, a molar ratio of acylating agent to compound of formula
(LIX) of from 1:1 to 10:1 is preferred. Where R.sup.3 in the
compound of formula (LIX) is a hydrogen atom, the group R.sup.3 O
may also be acylated in the course of this reaction.
The reaction will take place over a wide range of temperatures and
the particular temperature chosen is not critical. We generally
prefer to carry out the acylation reaction at a temperature within
the range from 0.degree. C. to 100.degree. C. The time required for
the reaction may vary over a wide range, depending upon many
factors, notably the nature of the reagents and the reaction
temperature; however, at a temperature within the preferred range,
a period of from 5 minutes to 20 hours will normally suffice.
Step F3
In this step, which is an alternative to step F2, a 2H-chromene
compound of formula (LXI) is prepared by dehydrating the
4-hydroxychroman (LIX).
The dehydration reaction may be achieved in the presence or absence
of a dehydrating agent or dehydrating catalyst. Suitable
dehydrating agents and catalysts include, for example: inorganic
acids, such as hydrochloric acid, sulfuric acid, nitric acid or
phosphoric acid; organic carboxylic acids, such as acetic acid,
tartaric acid or maleic acid; organic sulfonic acids, such as
p-toluenesulfonic acid, naphthalenesulfonic acid or methanesulfonic
acid; inorganic salts, such as ammonium chloride or calcium
chloride; phosphorus pentoxide; polyphosphoric acid; silica gel;
and alumina. Of these, we prefer an organic carboxylic acid such as
acetic acid or an organic sulfonic acid, such as p-toluenesulfonic
acid.
It is not always necessary to employ a solvent in this reaction;
however, where a solvent is used, its nature is not particular
critical, provided that is does not interfere with the reaction.
Examples of suitable solvents include: alcohols, such as methanol,
ethanol or isopropanol; ketones, such as acetone or methyl ethyl
ketone; ethers, such as diethyl ether, tetrahydrofuran or dioxane;
aromatic hydrocarbons, such as benzene, toluene or xylene;
aliphatic hydrocarbons, such as hexane, cyclohexane or heptane;
halogenated hydrocarbons, especially halogenated aliphatic
hydrocarbons, such as methylene chloride or chloroform; organic
carboxylic acids, such as acetic acid or propionic acid; organic
bases, such as pyridine or triethylamine; amides, such as
dimethylformamide or dimethylacetamide; sulfoxides, such as
dimethyl sulfoxide; sulfones, such as sulfolane; water; and
mixtures of any two or more thereof. Of these, we prefer aromatic
hydrocarbons, such as benzene, or organic acids, such as acetic
acid.
If a dehydrating agent or catalyst is employed, the relative
proportion of such agent or catalyst to the compound of formula
(LIX) is not critical, but we prefer to employ a molar ratio of
said agent or catalyst to said compound of formula (LIX) of from
0.01:1 to 10:1, more preferably from 0.1:1 to 3:1.
The reaction will take place over a wide range of temperatures and
the exact temperature chose is not particularly critical; however,
we generally prefer to carry out the reaction at a temperature in
the range from 20.degree. C. to 100.degree. C. The time required
for the reaction will vary, depending upon many factors, notably
the nature of the reagents and the reaction temperature; however,
at temperatures within the preferred range indicated above, a
period of from several minutes to 20 hours will normally
suffice.
Step F4
In this step, the 2H-chromene compound of formula (LXI) is prepared
from the 4-acyloxychroman of formula (LX) by elimination of an acid
of formula R.sup.11a OH (in which R.sup.11a is as defined
above).
This elimination reaction can be carried out in the presence or
absence of an acid-binding agent or catalyst. Examples of suitable
such agents and catalysts include: inorganic acids, such as
hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid;
organic carboxylic acids, such as acetic acid, tartaric acid or
maleic acid; organic sulfonic acids, such as p-toluenesulfonic
acid; naphthalenesulfonic acid or methanesulfonic acid; inorganic
salts, such as ammonium chloride or calcium chloride; organic
bases, such as pyridine or triethylamine; silica gel; and alumina.
Of these, we prefer an organic carboxylic or sulfonic acid, such as
acetic acid or p-toluenesulfonic acid.
It is not always necessary to employ a solvent for this elimination
reaction and, where a solvent is employed, its nature is not
critical, provided that it has no adverse effect on the reaction.
Suitable solvents include, for example: alcohols, such as methanol,
ethanol or isopropanol; ketones, such as acetone or methyl ethyl
ketone; ethers, such as deithyl ether, tetrahydrofuran or dioxane;
aromatic hydrocarbons, such as benzene, toluene or xylene;
aliphatic hydrocarbons, such as hexane, cyclohexane or heptane;
halogenated hydrocarbons, such as methylene chloride or chloroform;
organic acids, such as acetic acid or propionic acid; organic
bases, such as pyridine or triethylamine; amides, such as
dimethylformamide or dimethylacetamide; sulfoxides, such as
dimethyl sulfoxide; sulfones, such as sulfolane; and water. Of
these, we prefer aromatic hydrocarbons (such as benzene) or organic
acids (such as acetic acid).
Where an acid-binding agent or catalyst is employed, the relative
proportions of such agent or catalyst and the compound of formula
(LX) are not particularly critical. We generally prefer to employ
the agent or catalyst and the compound of formula (LX) in a molar
ratio of from 0.01:1 to 10:1, more preferably from 0.1:1 to
3:1.
The reaction will take place over a wide range of temperatures and
the exact temperature chosen is not particularly critical. In
general, we prefer to carry out the reaction at a temperature
within the range from 0.degree. C. to 120.degree. C., more
preferably from 40.degree. C. to 100.degree. C. The time required
for the reaction may vary widely, depending upon many factors,
notably the nature of the reagents and the reaction temperature;
however, at a temperature within the preferred ranges indicated
above, a period of from several minutes to several days, commonly
from 10 minutes to 10 hours, will normally suffice.
Step F5
In this step, the chroman derivative of formula (XXXIV) is prepared
by the reductive hydrogenation of the 2H-chromene derivative of
formula (LXI).
Catalytic hydrogenation is preferably employed. Suitable catalysts
include, for example palladium-on-carbon, Raney nickel or platinum
oxide, of which palladium-on-carbon is preferred. The partial
pressure of hydrogen may vary widely, for example from 1 to 100
atmospheres (about 1 to 101 bars), more preferably from 1 to 6
atmospheres (about 1 to 6 bars). The reaction is preferably
effected in the presence of a solvent, the nature of which is not
critical, provided that it does not interfere with the reaction.
Suitable solvents include, for example: alcohols, such as methanol
or ethanol; aromatic hydrocarbons, such as benzene or toluene;
ethers, such as tetrahydrofuran; organic acids, such as acetic
acid; water; or a mixture of any two or more thereof.
The reaction will take place over a wide range of temperatures and
the exact temperature chosen is not particularly critical; however,
we generally prefer to carry out the reaction at a temperature from
room temperature to 50.degree. C. The time required for the
reaction may vary widely, depending upon many factors, notably the
nature of the reagents and the reaction temperature; however, at a
temperature within the indicated range, a period of from several
minutes to 20 hours will normally suffice.
The .alpha.-halocarboxylic acid derivative of formula (XXX) may
then be prepared as described in step A4 from this compound of
formula (XXXIV).
Steps F1, F3 (or F2+F4), F5, A4 and the final step for reacting the
.alpha.-halocarboxylic acid derivative (XXX) with thiourea to give
the desired thiazolidine derivative of the invention can, if
desired, be carried out in succession without intermediate
isolation of the products of any of these steps.
Moreover, these steps are not necessarily carried out in the
sequence described above and they may be carried out in any
appropriate order. For example, one suitable alternative sequence
would comprise: first, reducing the nitro group in the compound of
formula (XLIX) by a step analogous to step F5 to give the
corresponding amino compound; reducing the carbonyl group at the
4-position of the chroman ring by a step analogous to step F1 to
give a 4-hydroxychroman compound; dehydrating this 4-hydroxychroman
compound by a step analogous to step F3 (or acylating and then
eliminating the acid by steps analogous to steps F2 and F4), to
give a 2H-chromene compound; and finally hydrogenating the
2H-chromene compound by a step analogous to step F5.
Method G
This process is useful for converting a chroman derivative, such as
those prepared in steps E5 and E6 of Method E, having a carbonyl
group as W at the 4-position to the corresponding compound where W
is a methylene group. The compounds prepared as described in steps
E5 and E6 are first, if necessary, deprotected, to remove the
protecting group R.sup.30 at the 6-position. The resulting free
hydroxy group is then acylated.
The resulting compound then has its carbonyl group protected, as
described in step E2, to give a compound of formula (LXIII) or
(LXV). These compounds are then hydrogenated, to give the
corresponding compounds of formulae (LXIV) or (LXVI), as shown
below: ##STR517##
In the above formulae, R.sup.1 -R.sup.5 and Ar are as defined
above; s is 2, 3 or 4.
The hydrogenation is preferably effected in the presence of a
catalyst, preferably a nickel catalyst, such as Raney nickel.
The hydrogen partial pressure may vary widely, for example from 1
to 100 atmospheres (about 1 to 101 bars), more preferably from 1 to
6 atmospheres (about 1 to 6 bars).
The reaction is preferably effected in the presence of a solvent,
the nature of which is not critical, provided that it has no
adverse effect upon the reaction. Suitable solvents include, for
example: alcohols, such as methanol or ethanol; aromatic
hydrocarbons, such as benzene or toluene; ethers, such as
tetrahydrofuran; organic acids, such as acetic acid; water; and
mixtures of any two or more thereof.
The reaction will take place over a wide range of temperatures, for
example from room temperature to 50.degree. C. The time required
for the reaction will vary, depending upon many factors, notably
the nature of the reagents and the reaction temperature, but a
period of from several minutes to 20 hours will normally
suffice.
The resulting compounds of formulae (LXIV) and (LXVI) may
thereafter be treated by any of the appropriate processes described
above to give the desired compounds of formula (II).
Method H
This method can be used to prepare compounds of formula (XIII),
having a group L at the 2-position of the chroman ring and where W
is a carbonyl group, as illustrated in the following reaction
scheme: ##STR518##
In the above formulae, R.sup.2 -R.sup.5, U, L, n, Ar, R.sup.7a, X
and A are as defined above.
Preferably, L represents a group of formula -OR.sup.3 and U
represents a methylene group. However, if desired, L, the carbon
atom to which it is attached and U may together represent a double
bond.
Step H1
In this step, the compound of formula (XLVII) is reacted with a
compound of formula (LXX):
(in which Ar, n and X are as defined above), followed by treatment
with an organic base, such as sodium ethoxide or potassium
t-butoxide. The reaction is otherwise similar to that of step C2 of
Method C and may be carried out under the same reaction
conditions.
Step H2
This is equivalent to step A3 and may be carried out using the same
reagents and under the same reaction conditions.
Step H3
This is equivalent to step A4 of Method A and may be carried out
using the same reagents under the same reaction conditions.
Of Methods A-H, Methods A, B, C, D, E, F and H are preferred,
Methods A, C, D, E, F and H being more preferred and a combination
of Methods D, F and A being most preferred. A particularly
preferred combination of reactions comprises steps F1, F3 or F2
plus F4), F5, A4 and finally reaction with thiourea to give a
compound of formula (I) in which R.sup.7 is R.sup.7a and R.sup.6 is
a hydrogen atom. In particular, we prefer this sequence of steps
where Ar represents a p-phenylene group.
In the compounds of formula (II), the carbon atom at the 2-position
of the chroman ring and the carbon atom to which the substituents
X, A and R.sup.7a are attached are both asymmetric and accordingly
a number of isomers are possible. The present invention envisages
both the individual isolated isomers as well as mixtures thereof.
Individual isomers may be prepared by stereospecific synthesis
techniques or by separation of mixtures of isomers. Alternatively,
the mixtures of isomers may be employed as such.
We have found that the .alpha.-halocarboxylic acid derivatives of
formula (II) have the ability to lower the levels of blood lipid
peroxides, blood triglycerides and blood cholesterol, indicating
that, in addition to their use as intermediates in the preparation
of the compounds of the invention, they may also have in themselves
therapeutic value in the treatment of hyperlipemia.
The compounds of formula (II) prepared as described above can, if
desired, be converted to various of their hydrolysis products or
may be transesterified or converted to salts, for example such
metal salts as the sodium, potassium, calcium or aluminum salts.
Alternatively, they can be converted from metal salts or from
compounds having free hdyroxyphenyl groups or free carboxy groups
to derivatives thereof, for example as follows:
Compounds in which R.sup.3 represents a hydrogen atom and A
represents a carboxy group can be prepared by hydrolysis of the
corresponding compound of formula (II) in which, for example,
R.sup.3 represents an acyl group and A represents an alkoxycarbonyl
group. This reaction is preferably effected in the presence of a
base, for example: an inorganic base, such as an alkali metal
carbonate (e.g. sodium carbonate or potassium carbonate) or an
alkali metal hydroxide (e.g. sodium hydroxide or potassium
hydroxide); or an organic base, such as an alkali metal alkoxide
(e.g. sodium methoxide, sodium ethoxide or potassium t-butoxide).
The reaction is preferably effected in the presence of a solvent,
the nature of which is not critical, provided that it has no
adverse effect upon the reaction. Suitable solvents include: lower
alcohols, such as methanol or ethanol; ethers, such as
tetrahydrofuran or dioxane; water; or mixtures of any two or more
thereof.
The molar ratio of the compound of formula (II) to the base is
preferably from 1:1 to 1:5, more preferably from 1:2 to 1:3.
Although the reaction conditions, particularly the reaction
temperature and time, may vary depending upon a number of factors,
particularly the natures of the starting material, base and solvent
employed, the reaction is generally carried out at a temperature of
from -10.degree. C. to +30 C., more preferably from 0.degree. C. to
10.degree. C., and the reaction time is generally from several
minutes to several tens of hours.
The compound of formula (II) in which R.sup.3 represents a hydrogen
atom and A represents an alkoxycarbonyl group can be prepared by
solvolysis of the corresponding compound in which R.sup.3
represents an acyl group and A represents an alkoxycarbonyl group.
This is carried out in the presence of a base, preferably an alkali
metal alkoxide, such as sodium methoxide, sodium ethoxide or
potassium t-butoxide. The reaction is preferably effected in the
presence of a solvent, for example: an alcohol, such as methanol,
ethanol, propanol, isopropanol or t-butanol; an ether, such as
tetrahydrofuran or dioxane; or a mixture of any two or more
thereof. It the alkoxycarbonyl group represented by A in the
starting material is to be kept intact, it is preferred that the
alkali metal alkoxide should be the alkoxide corresponding to this
alkoxycarbonyl group and that the solvent should be an alcohol,
which likewise corresponds to the alkoxycarbonyl group. However,
the alkoxycarbonyl group in the starting material may, if desired,
be converted into any other alkoxycarbonyl group by suitable choice
of the alkali metal alkoxide and the alcohol solvent.
The molar ratio of the compound of formula (II) to the base is
preferably from 1:1 to 1:3, more preferably from 1:1 to 1:2. The
reaction conditions, especially the reaction temperature and
reaction time, may vary, depending upon a number of factors,
particularly the natures of the starting materials, bases and
solvents employed, but the reaction is preferably carried out at a
temperature of from -10.degree. C. to +30.degree. C., more
preferably from 0.degree. to 10.degree. C., for a period of from
several minutes to several tens of hours.
Compounds of formula (II) in which R.sup.3 represents an acyl group
and A represents a carboxy group may be prepared by hydrolysis of
the corresponding compound of formula (II) in which R.sup.3
represents an acyl group and A represents an alkoxycarbonyl group.
In this case, the hydrolysis is effected in the presence of an
inorganic base (for example an alkali metal carbonate, such as
sodium carbonate or potassium carbonate, or an alkali metal
hydroxide, such as sodium hydroxide or potassium hydroxide) or in
the presence of another base such as an alkali metal alkoxide (for
example sodium methoxide, sodium ethoxide or potassium t-butoxide).
This reaction is preferably effected in the presence of a solvent,
for example: a lower alcohol, such as methanol or ethanol; an
ether, such as tetrahydrofuran or dioxane; water; or a mixture of
any two or more thereof. The molar ratio of the compound of formula
(II) to the base is preferably from 1:1 to 1:5, more preferably
from 1:1 to 1:2. The reaction conditions, particularly the reaction
temperature and time, may vary depending upon a number of factors,
especially the natures of the starting materials, bases and
solvents employed, but the reaction is normally effected at a
temperature of from -10.degree. C. to +30.degree. C., more
preferably from 0.degree. to 10.degree. C. for a period of from
several minutes to several tens of hours.
Of the compounds of formula (II) which exhibit the therapeutic
effects mentioned above and which also form part of the present
invention, preferred compounds are those listed below in Table
27.
In this Table, the abbreviations used are as previously defined in
relation to Tables 1-26.
Compounds of formula (II-27): ##STR519## are as defined in Table
27:
TABLE 27
__________________________________________________________________________
Cpd. No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 R.sup.5 W n Ar X A
__________________________________________________________________________
1001 Me Me H Me Me ##STR520## 1 6-Me-1,3-Phn Cl COOEt 1002 Me Me Ac
Me Me ##STR521## 1 6-Me-1,3-Phn Cl COOEt 1003 Me Me H Me Me
##STR522## 1 6-Me-1,3-Phn Cl COOEt 1004 Me Me Ac Me Me ##STR523## 1
6-Me-1,3-Phn Cl COOEt 1005 Me Me H Me Me ##STR524## 1 2,5-Pydi Cl
COOEt 1006 Me Me Ac Me Me ##STR525## 1 2,5-Pydi Cl COOEt 1007 Me Me
H Me Me ##STR526## 1 2,5-Pydi Cl COOEt 1008 Me Me Ac Me Me
##STR527## 1 2,5-Pydi Cl COOEt 1009 Me H H .sub.- t-Bu H ##STR528##
1 6-Me-1,3-Phn Cl COOEt 1010 Me H Ac .sub.- t-Bu H ##STR529## 1
6-Me-1,3-Phn Cl COOEt 1011 Me H H .sub.- t-Bu H ##STR530## 1
6-Me-1,3-Phn Cl COOEt 1012 Me H Ac .sub.- t-Bu H ##STR531## 1
6-Me-1,3-Phn Cl COOEt 1013 Me H H .sub.- t-Bu H ##STR532## 1
2,5-Pydi Cl COOEt 1014 Me H Ac .sub.- t-Bu H ##STR533## 1 2,5-Pydi
Cl COOEt 1015 Me H H .sub.- t-Bu H ##STR534## 1 2,5-Pydi Cl COOEt
1016 Me H Ac .sub.- t-Bu H ##STR535## 1 2,5-Pydi Cl COOEt 1017 Me H
Ac TMB H ##STR536## 1 p-Phn Cl COOEt 1018 Me H Ac TMB H ##STR537##
1 p-Phn Cl COOEt 1019 Me H Ac TMB H ##STR538## 1 6-Me-1,3-Phn Cl
COOEt 1020 Me H Ac TMB H ##STR539## 1 6-Me-1,3-Phn Cl COOEt 1021 Me
H Ac TMB H ##STR540## 1 2,5-Pydi Cl COOEt 1022 Me H Ac TMB H
##STR541## 2 p-Phn Cl COOMe 1023 Et Me Boz Me Me ##STR542## 1
5-Me-1,3-Phn Cl COOH 1024 .sub.- iBu Me 4-MeBoz Me H ##STR543## 1
2,5-Pydi Cl COOHN.sub.4 1025 -nPn Me Ac Me Me ##STR544## 1 2,5-Pydi
Cl COOMe 1026 Hx Me Ac Me Me ##STR545## 1 p-Phn Cl COOEt 1027
.sub.- iHx Me Ac Me Me ##STR546## 1 p-Phn Cl COOMe 1028 Hx Me Ac Me
Me ##STR547## 1 6-Me-1,3-Phn Cl COOH 1029 Hp H H .sub.- tBu H
##STR548## 1 2,5-Pydi Cl COOEt 1030 Oc Me Ac Me Me ##STR549## 1
p-Phn Cl COOEt 1031 Oc Me Ac Me Me ##STR550## 1 p-Phn Cl COOEt 1032
Oc Me Ac Me Me ##STR551## 1 6-Me-1,3-Phn Cl COOEt 1033 Oc Me Ac Me
Me ##STR552## 1 6-Me-1,3-Phn Cl COOEt 1034 Oc Me Ac Me Me
##STR553## 1 2,5-Pydi Cl COOEt 1035 Oc Me Ac Me Me ##STR554## 1
2,5-Pydi Cl COOEt 1036 Oc H Ac .sub.- t-Bu H ##STR555## 1 p-Phn Cl
COOEt 1037 Oc H Ac .sub.- t-Bu H ##STR556## 1 p-Phn Cl COOEt 1038
Oc H Ac .sub.- t-Bu H ##STR557## 1 6-Me-1,3-Phn Cl COOEt 1039 Oc H
Ac .sub.- t-Bu H ##STR558## 1 6-Me-1,3-Phn Cl COOEt 1040 Oc H Ac
.sub.- t-Bu H ##STR559## 1 2,5-Pydi Cl COOEt 1041 Oc H Ac .sub.-
t-Bu H ##STR560## 1 2,5-Pydi Cl COOEt 1042 Oc H Ac TMB H ##STR561##
1 p-Phn Cl COOEt 1043 Oc H Ac TMB H ##STR562## 1 p-Phn Cl COOEt
1044 Oc H Ac TMB H ##STR563## 1 6-Me-1,3-Phn Cl COOEt 1045 Oc H Ac
TMB H ##STR564## 1 6-Me-1,3-Phn Cl COOEt 1046 Oc H Ac TMB H
##STR565## 1 2,5-Pydi Cl COOEt 1047 Oc H Ac TMB H ##STR566## 1
2,5-Pydi Cl COOEt
1048 5,5-DMH Me Ac Me Me ##STR567## 1 p-Phn Cl COOEt 1049 Bz .sub.-
iPr H .sub.- iPr H ##STR568## 1 p-Phn Cl COOEt 1050 Nn Me H Me H
##STR569## 1 p-Phn Cl COOEt 1051 Dc Me Ac MeO MeO ##STR570## 1
p-Phn Cl COOEt 1052 3,7-DMO Me H Me Me ##STR571## 1 p-Phn Cl COOEt
1053 3,7-DMO Me Ac Me Me ##STR572## 1 p-Phn Cl COOEt 1054 3,7-DMO
Me Ac Me Me ##STR573## 1 p-Phn Cl COOEt 1055 3,7-DMO Me Ac Me Me
##STR574## 1 6-Me-1,3-Phn Cl COOEt 1056 3,7-DMO Me Ac Me Me
##STR575## 1 6-Me-1,3-Phn Cl COOEt 1057 3,7-DMO Me Ac Me Me
##STR576## 1 2,5-Pydi Cl COOEt 1058 3,7-DMO Me Ac Me Me ##STR577##
1 2,5-Pydi Cl COOEt 1059 3,7-DMO H H .sub.- tBu H ##STR578## 1
p-Phn Cl COOEt 1060 3,7-DMO H Ac .sub.- tBu H ##STR579## 1 p-Phn Cl
COOEt 1061 3,7-DMO H H .sub.- tBu H ##STR580## 1 p-Phn Cl COOEt
1062 3,7-DMO H Ac .sub.- tBu H ##STR581## 1 p-Phn Cl COOEt 1063
3,7-DMO H H .sub.- tBu H ##STR582## 1 6-Me-1,3-Phn Cl COOEt 1064
3,7-DMO H Ac .sub.- tBu H ##STR583## 1 6-Me-1,3-Phn Cl COOEt 1065
3,7-DMO H H .sub.- tBu H ##STR584## 1 6-Me-1,3-Phn Cl COOEt 1066
3,7-DMO H Ac .sub.- tBu H ##STR585## 1 6-Me-1,3-Phn Cl COOEt 1067
3,7-DMO H Ac .sub.- tBu H ##STR586## 1 2,5-Pydi Cl COOEt 1068
3,7-DMO H Ac .sub.- tBu H ##STR587## 1 2,5-Pydi Cl COOEt 1069
3,7-DMO H Ac TMB H ##STR588## 1 p-Phn Cl COOEt 1070 3,7-DMO H Ac
TMB H ##STR589## 1 p-Phn Cl COOEt 1071 3,7-DMO H Ac TMB H
##STR590## 1 6-Me-1,3-Phn Cl COOEt 1072 3,7-DMO H Ac TMB H
##STR591## 1 6-Me-1,3-Phn Cl COOEt 1073 3,7-DMO H AC TMB H
##STR592## 1 2,5-Pydi Cl COOEt 1074 3,7-DMO H Ac TMB H ##STR593## 1
2,5-Pydi Cl COOEt 1075 3,7-DMO H Boz TMB H ##STR594## 1 p-Phn Cl
COOEt 1076 3,7-DMO H Ac Me H ##STR595## 1 p-Phn Cl COOH 1077
7,7-DMO Me H Me Me ##STR596## 1 p-Phn Cl COOEt 1078 7,7-DMO Me Ac
Me Me ##STR597## 1 p-Phn Cl COOEt 1079 7,7-DMO Me H Me Me
##STR598## 1 p-Phn Cl COOEt 1080 7,7-DMO Me Ac Me Me ##STR599## 1
p-Phn Cl COOEt 1081 7,7-DMO Me Ac Me Me ##STR600## 1 6-Me-1,3-Phn
Cl COOEt 1082 7,7-DMO Me Ac Me H ##STR601## 1 6-Me-1,3-Phn Cl COOEt
1083 7,7-DMO Me Ac Me H ##STR602## 1 2,5-Pydi Cl COOEt 1084 7,7-DMO
Me Ac Me H ##STR603## 1 2,5-Pydi Cl COOEt 1085 7,7-DMO H Ac .sub.-
tBu H ##STR604## 1 p-Phn Cl COOEt 1086 7,7-DMO H Ac .sub.- tBu H
##STR605## 1 p-Phn Cl COOEt 1087 7,7-DMO H Ac TMB H ##STR606## 1
p-Phn Cl COOEt 1088 Bz Me H Me Me ##STR607## 1 p-Phn Cl COOEt 1089
Bz Me Ac Me Me ##STR608## 1 p-Phn Cl COOEt 1090 Bz Me H Me Me
##STR609## 1 p-Phn Cl COOEt 1091 Bz Me Ac Me Me ##STR610## 1 p-Phn
Cl COOEt 1092 Bz H H .sub.- tBu H ##STR611## 1 p-Phn Cl COOEt 1093
Bz H H TMB H
##STR612## 1 p-Phn Cl COOEt 1094 Me Me HOOCCH.sub.2 Me Me
##STR613## 1 p-Phn Cl COOEt 1095 Me Me EtOOCCH.sub.2 Me Me
##STR614## 1 p-Phn Cl COOEt 1096 Me H HOOCCH.sub.2 .sub.- tBu H
##STR615## 1 2,5-Pydi Cl COOH 1097 3,7-DMO H HOOC(CH.sub.2).sub.2
.sub.- tBu H ##STR616## 2 p-Phn Br COOH 1098 Me H HOOCCMe.sub.2 TMB
H ##STR617## 1 6-Me-1,3-Phn Cl COOPr
__________________________________________________________________________
In addition, other compounds useful as intermediates are shown in
Tables 28 and 29, the abbreviations used again being as defined in
relation to Tables 1-26.
Compounds of formulae (XIII-28) and (XIII-29): ##STR618##
are as defined in Table 27 and 28, respectively:
TABLE 28
__________________________________________________________________________
Cpd. No. L U R.sup.2 R.sup.3 R.sup.4 R.sup.5 n Ar X A
__________________________________________________________________________
2001 OH > CH.sub. 2 Me H Me Me 1 p-Phn Cl COOH 2002 OH >
CH.sub. 2 Me Ac Me Me 1 p-Phn Cl COOEt 2003 OH > CH.sub. 2 Me H
Me Me 2 p-Phn Cl COOH 2004 OH > CH.sub. 2 Me H Me Me 1
6-Me-1,3-Phn Cl COOMe 2005 OH > CH.sub. 2 Me Ac Me Me 1
6-Me-1,3-Phn Cl COOEt 2006 OH > CH.sub. 2 Me H Me Me 1 2,5-Pydi
Cl COOH 2007 OH > CH.sub. 2 Me Ac Me Me 1 2,5-Pydi Cl COO
.sub.-iPr 2008 OH > CH.sub. 2 H H .sub.-tBu H 1 p-Phn Cl COOH
2009 OH > CH.sub. 2 H Ac .sub.-tBu H 1 p-Phn Cl COOEt 2010 OH
> CH.sub. 2 H H .sub.-tBu H 1 6-Me-1,3-Phn Cl COOH 2011 OAc >
CH.sub. 2 H Ac .sub.-tBu H 1 6-Me-1,3-Phn Cl COO- .sub.-tBu 2012 OH
> CH.sub. 2 H H .sub.-tBu H 1 2,5-Pydi Cl COOH 2013 OH >
CH.sub. 2 H Ac .sub.-tBu H 1 2,5-Pydi Cl COOPh 2014 OH > CH.sub.
2 H H TMB H 1 p-Phn Cl COOH 2015 OH > CH.sub. 2 H H TMB H 1
6-Me-1,3-Phn Cl COOH 2016 OH > CH.sub. 2 H H TMB H 1 2,5-Pydi Cl
COOH
__________________________________________________________________________
TABLE 29
__________________________________________________________________________
Cpd. No. R.sup.2 R.sup.3 R.sup.4 R.sup.5 n Ar X A
__________________________________________________________________________
2017 Me H Me Me 1 p-Phn Cl --COOH 2018 Me Ac Me Me 1 p-Phn Cl
--COOEt 2019 Me H Me Me 1 6-Me-1,3-Phn Cl --COOH 2020 Me Ac Me Me 1
6-Me-1,3-Phn Cl --COOMe 2021 Me H Me Me 1 2,5-Pydi Cl --COOH 2022
Me Ac Me Me 1 2,5-Pydi Cl --COOEt 2023 H H .sub.- tBu H 1 p-Phn Cl
--COOH 2024 H H .sub.- tBu H 1 6-Me-1,3-Phn Cl --COOH 2025 H H
.sub.- tBu H 1 2,5-Pydi Cl --COOH 2026 H H TMB H 1 p-Phn Cl --COOH
2027 H H TMB H 1 p-Phn Cl --COO .sub.- iBu 2028 Me HOOC--CH.sub.2
-- Me Me 1 p-Phn Cl --COOH 2029 Me EtOOC--CH.sub.2 -- Me Me 1 p-Phn
Cl --COOEt 2030 Me EtOOC--CH.sub.2 -- Me Me 1 2,5-Pydi Cl --COOEt
2031 H HOOC--CH.sub.2 -- .sub.- tBu H 1 p-Phn Cl --COOH 2032 H
EtOOC--CH.sub.2 -- .sub.- tBu H 1 6-Me-1,3-Phn Cl --COOEt 2033 H
HOOC--CH.sub.2 -- TMB H 1 p-Phn Cl --COOH 2034 H BuOOC--CH.sub.2 --
TMB H 1 p-Phn Cl COOBu 2035 H HOOC--CH.sub.2 -- TMB H 1 p-Phn Br
--COOH 2036 Me HOOCCMe.sub.2 -- Me Me 1 p-Phn Cl --COOH 2037 H
HOOCCMe.sub.2 -- .sub.- tBu H 1 p-Phn Cl --COOH 2038 H
HOOCCMe.sub.2 -- TMB H 1 p-Phn Cl --COOH 2039 H EtOOCCMe.sub.2 --
Me H 1 p-Phn Cl --COOEt
__________________________________________________________________________
The compounds of the invention have shown a very strong ability to
inhibit the oxidation of unsaturated fatty acids and their esters
(such as linolic acid and ethyl linolate) and, accordingly, it is
expected that these compounds will be able to prevent the oxidation
of phospholipids containing a high content of unsaturated fatty
acids from oxidation, even in vivo.
The compounds of the invention have been shown to have a very
strong ability to lower the level of lipid peroxides, as
demonstrated, inter alia, by the test against rat liver microsomal
lipid peroxidation described in Biochem. Biphys. Res. Commun., 95,
734 (1980). In addition, in experiments using alloxan-induced
hyperlipaemic ice, the compounds have demonstrated the ability to
lower blood lipid peroxide, triglyceride and cholesterol levels.
The compounds have also shown the ability to lower blood sugar
levels in a test using genetically diabetic mice of the KK strain.
Moreover, the compounds of the invention are less toxic than many
known compounds to experimental animals such as rats or mice and
result in little anorexia, inhibition of body weight increase and
liver hypertrophy.
Accordingly, it is considered that the compounds of the present
invention will be useful for the therapeutic treatment of human
hyperlipaemia, diabetes and complications thereof, especially
diabetes mellitus. The compounds of the invention may be
administered orally, for example in the form of tablets, capsules,
powders or granules, or parenterally, for example by injection or
in the form of a suppository. The recommended dosage will, of
course, vary depending upon the age and body weight of the patient
as well as the nature and severity of the disease. However, for an
adult human patient, a daily dose of from 50 mg to 5 g (which may
be administered in a single dose or in divided doses) is
recommended in the treatment of hyperlipaemia, diabetes mellitus
and complications thereof.
The following Examples illustrate the preparation of various of the
compounds of the present invention. Preparation of various of the
starting materials employed in the Examples is illustrated in the
subsequent Preparations. The subsequent Test Examples illustrate
the valuable biological properties of these compounds.
In the nuclear magnetic resonance spectra reported in the Examples
and Preparations, the abbreviation "nd" means that precise
identification of the signal was not possible because of overlap by
other signals or the absorption of the solvent.
EXAMPLE 1
59]4-(6-Hydroxy-2-isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)benzyl]
thiazolidine -2,4-dione (Step D4)
A mixture of 0.5 g of ethyl
3-[4-(6-acetoxy-2-isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)phenyl
]-2-chloropropionate (prepared as described in Preparation 9), 0.2
g of thiourea and 0.8 g of sulfolane was heated at
120.degree.-135.degree. C. for 4 hours under a nitrogen stream. A
mixture of 1 ml of concentrated hydrochloric acid, 1 ml of water
and 5 ml of ethylene glycol monomethyl ether was then added to the
reaction mixture, and the mixture was heated under reflux for 6
hours. The reaction mixture was then poured into water and
extracted with ethyl acetate. The ethyl acetate extract was dried
over anhydrous sodium sulfate. The solvent was distilled off and
the residue was purified by preparative silica gel thin layer
chromatography using a 1:1 by volume mixture of hexane and ethyl
acetate as developing solvent, to give the title compound,
softening at 70.degree.-78.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.97 (6H, doublet, J+6 Hz);
1.5-2.1 (3H, nd);
2.12 (3H, singlet);
2.21 (3H, singlet);
2.53 (3H, singlet);
2.77 .delta. 2.99 (2H, AB type, J=16 Hz);
2.8-3.2 (1H, nd);
3.41 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.06 (2H, AB type, J=10 Hz);
4.43 (1H, doublet of doublets, j=4 .delta. 9 Hz);
4.6-5.3 (1H, broad singlet, disappeared on adding heavy water);
6.81 (2H, doublet, J=9 Hz);
7.12 (2H, doublet, J=9 Hz);
8.7-9.3 (1H, broad singlet, disappeared on adding heavy water).
EXAMPLE 2
5-[4-(6-Acetoxy-5,7,8-trimethyl-2-octylchroman-2-yl-methoxy)benzyl]thiazoli
dine-2,4-dione
A mixture of 2.1 g of ethyl
3-[4-(6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)phenyl]-2-chlor
opropionate (prepared as described in Preparation 18), 0.35 g of
thiourea and 2.5 ml of sulfolane was heated for 7 hours at
120.degree.-130.degree. C. under a nitrogen atmosphere. The
reaction mixture was then dissolved in benzene. The benzene
solution was washed with water and dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure. The
residue was purified by silica gel column chromatography, eluted
with a 10:1 by volume mixture of benzene and ethyl acetate, to give
the title compound as a slightly yellow, foamy solid.
Rf value on silica gel thin layer chromatography=0.55 (developing
solvent, benzene:ethyl acetate=4:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.7-1.0 (3H, multiplet);
1.1-2.0 (16H, multiplet);
1.97 (3H, singlet);
2.03 (3H, singlet);
2.08 (3H, singlet);
2.31 (3H, singlet);
2.60 (2H, broad triplet, J=6 Hz);
3.03 (1H, doublet of doublets, J=10 .delta. 15 Hz);
3.44 (1H, doublet of doublets, J=3 .delta. 15 Hz);
3.92 (2H, singlet);
4.45 (1H, doublet of doublets, J=3 .delta. 10 Hz);
6.85 (2H, doublet, J=9 Hz);
7.13 (2H, doublet, J=9 Hz);
8.0-8.9 (1H, broad, disappeared on adding heavy water).
EXAMPLE 3
5-[4-(6-Hydroxy-5,7,8-trimethyl-2-octylchroman-2-yl-methoxy)benzyl]thiazoli
dine-2,4-dione
A mixture of 2.1 g of ethyl
3-[4-(6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)phenyl]-2-chlor
opropionate (prepared as described in Preparation 18). 0.35 g of
thiourea and 2.5 ml of sulfolane was heated for 7 hours at
120.degree.-130.degree. C. under a nitrogen atmosphere. A mixture
of 3.6 ml of 2N aqueous hydrochloric acid and 5 ml of ethylene
glycol monomethyl ether was then added to the reaction mixture,
after which it was heated for a further 5 hours at
85.degree.-90.degree. C. The reaction mixture was then poured into
water and extracted with benzene. The benzene extract was washed
with water and dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure and the residue was purified
by silica gel column chromatography, using a 10:1 by volume mixture
of benzene and ethyl acetate as eluent, to give the title compound
as a slightly yellow, foamy solid.
Rf value on silica gel thin layer chromatography=0.43 (trailing)
(developing solvent, benzene:ethyl acetate=4:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.7-1.0 (3H, multiplet);
1.1-2.1 (16H, multiplet);
2.10 (6H, singlet);
2.15 (3H, singlet);
2.61 (2H, broad triplet, J=6 Hz);
3.05 (1H, doublet of doublets, J=10 .delta. 15 Hz);
3.42 (1H, doublet of doublets, J=3 .delta. 15 Hz);
3.92 (2H, singlet);
4.22 (1H, singlet, disappeared on adding heavy water);
4.47 (1H, doublet of doublets, J=3 .delta. 10 Hz);
6.85 (2H, doublet, J=9 Hz);
7.13 (2H, doublet, J=9 Hz);
8.33 (1H, broad singlet, disappeared on adding heavy water).
EXAMPLE 4
5-[4-(6-Acetoxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)-chroman-2-ylmethoxy)b
enzyl]thiazolidine -2,4dione
The procedure described in Example 2 was repeated, but using 7.0 g
of ethyl
3-{4-[6-acetoxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]p
henyl}-2-chloropropionate (prepared as described in Preparation
23), 1.2 g of thiourea and 9 ml of sulfolane, to give the title
compound as slightly yellow glassy solid, softening at
75.degree.-80.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.79 (9H, singlet);
1.36 (6H, singlet);
1.45 (3H, singlet);
1.66-2.28 (2H, nd);
1.80 (2H, singlet);
2.29 (3H, singlet);
2.73 (2H, broad triplet, J=6 Hz);
3.28 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.45 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.93 (2H, AB type, J=9 Hz);
4.49 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.75 (1H, singlet);
6.86 (1H, singlet);
6.90 (2H, doublet, J=9 Hz);
7.13 (2H, doublet, J=9 Hz);
8.1-8.7 (1H, broad, disappeared on adding heavy water).
EXAMPLE 5
5-{4-[6Hydroxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)-chroman-2-ylmethoxy]be
nzyl}thiazolidine-2,4-dione
The procedure described in Example 3 was repeated, but using 7.0 g
of ethyl
3-{4-[6-acetoxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]p
henyl}-2-chloropropionate (prepared as described in Preparation
23), 1.2 g of thiourea, 9 ml of sulfolane, 13 ml of 2N hydrochloric
acid and 20 ml of ethylene glycol monomethyl ether, to give the
title compound as a slightly yellow glassy solid, softening at
80.degree.-85.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.78 (9H, singlet);
1.41 (9 H, singlet);
1.60-2.30 (2H, nd);
1.91 (2H, singlet);
2.67 (2H, broad triplet, J=6.5 Hz);
3.07 (1H, doublet of doublets, J=10 .delta. 14 Hz);
3.45 (1H, doublet of doublets, J=4 and 14 Hz);
3.93 (2H, AB type, J=9 Hz);
4.45 (1H, singlet, disappeared on adding heavy water);
4.49 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.34 (1H, singlet);
6.77 (1H, singlet);
6.88 (2H, doublet, J=9 Hz);
7.17 (2H, doublet, J=9 Hz);
8.4 (1H, broad singlet, disappeared on adding heavy water).
EXAMPLE 6
5-{4-[6-Acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmeth
oxy]benzyl}thiazolidine -2,4-dione
The procedure described in Example 2 was repeated, but using 7.3 g
of ethyl
3-{4-[6-acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)
chroman-2-ylmethoxy]phenyl}-2-chloropropionate (prepared as
described in Preparation 25), 1.3 g of thiourea and 8 ml of
sulfolane, to give the title compound as a slightly yellow powder,
softening at 80.degree. -88.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.78 (9H, singlet);
1.37 (6H, singlet);
1.53 (3H, singlet);
1.83 (2H, singlet);
2.30 (3H, singlet);
2.70 (1H, doublet, J=17 Hz);
2.8-3.2 (1H, nd);
3.10 (1H, doublet, J=17 Hz);
3.45 (1H, doublet of doublets, J=4 .delta. 15 Hz);
4.00 .delta. 4.12 (2H, AB type, J=9 Hz);
4.48 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.85 (2H, doublet, J=9 Hz);
7.02 (1H, singlet);
7.17 (2H, doublet, J=9 Hz);
7.51 (1H, singlet);
8.3-9.0 (1H, broad, disappeared on adding heavy water).
EXAMPLE 7
5-{4-[6-Hydroxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmeth
oxy]benzyl}thiazolidine-2,4-dione
A mixture of 5.2 g of
5-{4-[6-acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)
chroman-2-ylmethoxy]-benzyl}-2-iminothiazolidin-4-one prepared as
described in Preparation 26), 16 ml of 2N hydrochloric acid and 25
ml of ethylene glycol monomethyl ether was heated for 6 hours at
85.degree.-90.degree. C. under a nitrogen atmosphere. The reaction
mixture was then poured into water and extracted with benzene. The
benzene extract was washed with water and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure and the residue was purified by silica gel column
chromatography, eluted with a 4:1 by volume mixture of benzene and
ethyl acetate, to give the title compound as a slightly yellow
foamy solid, softening at 100.degree.-105.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.77 (9H, singlet);
1.43 (6H, singlet);
1.52 (3H, singlet);
2.00 (2H, singlet);
2.70 (1H, doublet, J=17 Hz);
2.8-3.2 (1H, nd);
3.12 (1H, doublet, J=17 Hz);
3.43 (1H, doublet of doublets, J=4 .delta. 15 Hz);
4.00 .delta. 4.10 (2H, AB type, J=9 Hz);
4.49 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.1 (1H, broad singlet, disappeared on adding heavy water);
6.85 (2H, doublet, J=9 Hz);
6.93 (1H, singlet);
7.15 (2H, doublet, J=9 Hz);
7.30 (1H, singlet);
8.2-9.3 (1H, broad, disappeared on adding heavy water).
EXAMPLE 8
5-{4-[2-(3,7-Dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmeth
oxy]benzyl}thiazolidine-2,4-dione
The procedure described in Example 3 was repeated, but using 1.1 g
of ethyl
3-{4-[6-acetoxy-2-(3,7-dimethyloctyl)-5,7,8-trimethyl-4-oxochroman-2-ylmet
hoxy]phenyl}-2-chloropropionate (prepared as described in
Preparation 33), 0.2 g of thiourea, 1.5 ml of sulfolane, 5 ml of 2N
aqueous hydrochloric acid and 10 ml of ethylene glycol monomethyl
ether, to give the title compound, as a slightly yellow powder,
softening at 41.degree.-45.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.85 (9H, doublet, J=7 Hz);
1.0-2.0 (12H, multiplet);
2.13 (3H, singlet);
2.22 (3H, singlet);
2.55 (3H, singlet);
2.65-3.2 (3H, multiplet);
3.43 (1H, doublet of doublets, J=4 .delta. -Hz);
4.05 (2H, singlet);
4.35-5.3 (1H, broad, disappeared on adding heavy water);
4.46 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.83 (2H, doublet, J=9 Hz);
7.15 (2H, doublet, J=9 Hz);
8.0-9.5 (1H, broad, disappeared on adding heavy water).
EXAMPLE 9
5-[2-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)pyridin-5-ylmethyl]t
hiazolidine -2,4-dione
The procedure described in Example 3 was repeated, but using 3.8 g
of ethyl
3-[2-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)pyridin-5-yl]-2-chl
oropropionate (prepared as described in Preparation 38), 0.77 g of
thiourea, 5.0 ml of sulfolane, 4.5 ml of ethylene glycol monomethyl
ether, 1.5 ml of concentrated hydrochloric acid and 4.5 ml of
water, to give the title compound, softening at
87.degree.-94.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.38 (3H, singlet);
1.7-2.3 (2H, multiplet);
2.06 (3H, singlet);
2.09 (3H, singlet);
2.14 (3H, singlet);
2.63 (2H, broad triplet, J=6 Hz);
3.10 (1H, doublet of doublets, J=15 .delta. 7.5 Hz);
3.33 (1H, doublet of doublets, J=15 .delta. 4.5 Hz);
4.0-5.0 (1H, broad, disappeared on adding heavy water);
4.32 (3H, singlet);
4.47 (1H, doublet of doublets, J=7.5 .delta. 4.5 Hz);
6.75 (1H, doublet, J=9 Hz);
7.46 (1H, doublet of doublets, J=9 .delta. 3 Hz);
8.02 (1H, doublet, J=3 Hz).
EXAMPLE 10
5-[3-(7-t-Butyl-6-hydroxy-2-methyl-4-oxochroman-2-ylmethoxy)-4-methylbenzyl
]thiazolidine-2,4-dione
the procedure described in Example 3 was repeated, but using 2,4 g
of ethyl
3-[3-(6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy)
-4-methylphenyl]-2-chloropropionate (prepared as described in
Preparation 42), 0.7 g of thiourea, 5 ml of sulfolane, 10 ml of 2N
aqueous hydrochloric acid and 15 ml of ethylene glycol monomethyl
ether, to give the title compound.
Rf value on silica gel thin layer chromatography=0.44 (developing
solvent, benzene:ethyl acetate=1:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.40 (9H, singlet);
1.57 (3H, singlet);
2.14 (3H, singlet;
2.77 (1H, doublet, J=16 Hz);
3.01 (1H, doublet of doublets, J=10 .delta. 14 Hz);
3.07 (1H, doublet, J=16 Hz);
3.44 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.99 .delta. 4.13 (2H, AB type, J=10 Hz);
4.50 (1H, doublet of doublets, J=4 .delta. 10 Hz);
5.84 (1H, broad singlet, disappeared on adding heavy water);
6.6-6.85 (2H, nd);
6.91 (1H, singlet);
7.08 (1H, doublet, J=7.5 Hz);
7.32 (1H, singlet);
8.3-9.0 (1H, broad, disappeared on adding heavy water).
EXAMPLE 11
5-[4-(6-Hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidin
e-2,4-dione
The procedure described in Example 3 was repeated, but using 2.2 g
of ethyl
3-[4-(6-acetoxy-2-hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)
phenyl]-2-chloropropionate (prepared as described in Preparation
45), 0.8 g of thiourea, 4.5 g of sulfolane, 70 ml of ethylene
glycol monomethyl ether, 8 ml of water and 4 ml of 35% w/v aqueous
hydrochloric acid, to give the title compound, melting at
249.degree.-252.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 SO]
.delta.ppm:
2.25 (6H, singlet);
2.63 (3H, singlet);
2.7-3.8 (2H, nd);
4.88 (1H, doublet of doublets, J=4 .delta. 9 Hz);
5.11 (2H, singlet);
6.28 (1H, singlet);
7.05 (2H, doublet, J=9 Hz);
7.24 (2H, doublet, J=9 Hz);
8.3-8.7 (1H, broad singlet, disappeared on adding heavy water).
EXAMPLE 12
5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-5-methylthia
zolidine-2,4-dione
The procedure described in Example 3 was repeated, but using 1.17 g
of ethyl
3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chl
oro -2-methylpropionate (prepared as described in Preparation 46),
0.63 g of thiourea, 3 g of sulfolane, 10 ml of ethylene glycol
monomethyl ether, 3 ml of water and 2 ml of 35% w/v aqueous
hydrochloric acid, to give the title compound, softening at
69.degree.-72.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.40 (3H, singlet);
1.72 (3H, singlet);
1.6-2.3 (2H, nd);
2.10 (6H, singlet);
2.16 (3H, singlet);
2.62 (2H, broad triplet, J=7 Hz);
2.94 (1H, doublet, J=14 Hz);
3.24 (1H, doublet, J=14 Hz);
3.84 and 3.97 (2H, AB type, J=9 Hz);
4.40 (1H, broad singlet, disappeared on adding heavy water);
6.84 (2H, doublet, J=9 Hz);
7.13 (2H, doublet, J=9 Hz);
8.4-8.9 (1H, broad singlet, disappeared on adding heavy water).
EXAMPLE 13
5-{4-[6-Hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]b
enzyl}thiazolidine -2,4-dione
A mixture of 5 g of
5-[4-(6hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazol
idine-2,4-dione (prepared as described in Example 22 of copending
U.S. Ser. No. 644,996), 3 g of hydroxylamine hydrochloride, 50 g of
methanol and 3 g of pyridine was stirred for 1 week at room
temperature. At the end of this time, ethyl acetate and an aqueous
solution of potassium carbonate were added. The organic layer was
separated and dried over anhydrous sodium sulfate. The solvent was
distilled off and the residue was purified by silica gel column
chromatography, eluted with a 1:1 by volume mixture of hexane and
ethyl acetate, to give the title compound, softening at
84.degree.-100.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO]
.delta.ppm:
1.42 (3H, singlet);
2.09 (3H, singlet);
2.18 (3H, singlet);
2.48 (3H, singlet);
3.03 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.07 (2H, singlet);
3.43 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.05 (2H, singlet);
4.72 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.92 (2H, doublet, J=9 Hz);
7.21 (2H, doublet, J=9 Hz);
9.7-10.5 (1H, broad singlet, disappeared on adding heavy
water).
EXAMPLE 14
5-{4-[6-Hydroxy-4-(Z)-hydroxylimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]
benzyl}thiazolidine-2,4-dione
The title compound, softening at 100.degree.-105.degree. C., was
obtained from the fraction that was eluted following the reaction
containing the compound of Example 13 in the column chromatography
conducted in Example 13 and using the same eluent.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO].delta.
ppm:
1.46 (3H, singlet);
2.04 (3H, singlet);
2.18 (6H, singlet);
2.58 (1H, doublet, J=13 Hz);
2.87 (1H, doublet, J=13 Hz);
3.10 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.43 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.01 (2H, singlet);
4.74 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.92 (2H, doublet, J=9 Hz);
7.22 (2H, doublet, J=9 Hz);
9.4-10.6 (1H, broad singlet, disappeared on adding heavy
water).
EXAMPLE 15
5-{4-[6-Hydroxy-4-(Z)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]b
enzyl}thiazolidine -2,4-dione
27 mg of
59{4-[6-hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]
-benzyl }thiazolidine-2,4-dione (prepared as described in Example
13) was heated on an oil bath for 5 hours at
140.degree..div.5.degree. C. The reaction mixture was then
subjected to high pressure liquid chromatography, which confirmed
the presence of the title compound (the same compound as in Example
14).
EXAMPLE 16
5-{4-[6Hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]be
nzyl}thiazolidine -2,4-dione
62 mg of
5-{4-[6-hydroxy-4-(Z)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]
benzyl }-thiazolidine-2,4-dione (prepared as described in Example
14) were heated in an oil bath for 5 hours at
140.degree..+-.5.degree. C. The reaction mixture was subjected to
high pressure liquid chromatography, to confirm the presence of the
title compound (the same compound as described in Example 13).
EXAMPLE 17
5-{4-[6-Acetoxy-4-(E)-acetoxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy]b
enzyl}thiazolidine -2,4-dione
A mixture of 1 g of
5-{4-[6-hydroxy-4-(E)-hydroxyimino-2,5,7,8tetramethylchroman-2-ylmethoxy
]benzyl}thiazolidine-2,4-dione (prepared as described in Example
13), 1.3 g of acetic anhydride and 10 ml of pyridine was allowed to
stand for 8 days at room temperature, after which it was heated for
8 hours at 60.degree.-80.degree. C. An aqueous solution of
potassium carbonate and ethyl acetate were then added to the
reaction mixture. The organic layer was separated and dried over
anhydrous sodium sulfate. The solvent was distilled off and the
residue was purified by silica gel column chromatography, eluted
with a 4:1 by volume mixture of hexane and ethyl acetate, to give
the title compound, softening at 93.degree.-97.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.48 (3H, singlet);
2.07 (3H, singlet);
2.10 (3H, singlet);
2.22 (3H, singlet);
2.33 (3H, singlet);
2.42 (3H, singlet);
3.00 (1H, doublet, J=17 Hz);
3.26 (1H, doublet, J=17 Hz);
3.0-3.3 (1H, nd);
3.41 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.91 and 4.06 (2H, AB type, J=9 Hz);
4.47 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.84 (2H, doublet, J=9 Hz);
7.14 (2H, doublet, J=9 Hz).
EXAMPLE 18
5-{4-[6-Benzoyloxy-4-(E)-benzoyloxyimino-2,5,7,8tetramethylchroman-2-ylmeth
oxy]benzyl}thiazolidine-2,4-dione
A mixture of 1 g of
5-{4-[6-hydroxy-4-(E)-hydroxyimino-2,5,7,8tetramethylchroman-2-ylmethoxy
]benzyl}-thiazolidine-2,4-dione (prepared as described in Example
13), 1.7 g of benzoyl bromide, 10 ml of pyridine and 5 ml of
dimethylformamide was allowed to stand for 6 days at room
temperature, after which it was heated for 8 hours at
60.degree.-80.degree. C. An aqueous solution of potassium carbonate
and ethyl acetate were then added to the reaction mixture. The
organic layer was separated and dried over anhydrous sodium
sulfate. The solvent was distilled off and the residue was purified
by silica gel column chromatography eluted with a 4:3 by volume
mixture of hexane and ethyl acetate, to give the title compound,
softening at 101.degree.-107.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.55 (3H, singlet);
2.14 (6H, singlet);
2.58 (3H, singlet);
2.8-3.7 (4H, nd);
3.98 and 4.12 (2H, AB type, J=9 Hz);
4.45 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.84 (2H, doublet, J=9 Hz);
7.14 (2H, doublet, J=9 Hz);
7.3-7.8 (6H, multiplet);
7.9-8.5 (4H, multiplet).
EXAMPLE 19
5-{4-[2,5,7,8-Tetramethyl-6-nicotinoyloxy-4-(E)-nicotinoyloxyiminochroman-2
-ylmethoxy]benzyl}-thiazolidine-2,4-dione
A mixture of 1 g of
5-{4-[6-hydroxy-4-(E)-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmethoxy
]benzyl}thiazolidine-2,4-dione (prepared as described in Example
13), 1.1 g of nicotinoyl chloride hydrochloride, 12 ml of pyridine
and 12 ml of dimethylformamide was allowed to stand for 6 days at
room temperature, after which it was heated for 8 hours at
60.degree.-80.degree. C. An aqueous solution of potassium carbonate
and ethyl acetate were added to the reaction mixture. The organic
layer was separated and dried over anhydrous sodium sulfate. The
solvent was distilled off, and the residue was purified by silica
gel column chromatography eluted with a 2:3 by volume mixture of
hexane and ethyl acetate, followed by preparative thin layer silica
gel chromatography (developing solvent, hexane:ethyl acetate=1.10
by volume), to give the title compound, softening at
123.degree.-130.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.56 (3H, singlet);
2.13 (3H, singlet);
2.17 (3H, singlet);
2.57 (3H, singlet);
2.8-3.7 (4H, nd);
3.99 and 4.16 (2H, AB type, J=9 Hz);
4.45 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.84 (2H, doublet, J=9 Hz);
7.15 (2H, doublet, J=9 Hz);
7.4-7.7 (2H, multiplet);
8.3-8.7 (2H, multiplet);
8.7-9.0 (2H, multiplet);
9.2-9.6 (2H, multiplet);
10.0-11.0 (1H, broad, disappeared on adding heavy water).
EXAMPLE 20
5-{4-[7-t-Butyl-6hydroxy-4-(E)-hydroxyimino-2methylchroman-2-ylmethoxy]benz
yl}thiazolidine-2,4-dione
The procedure described in Example 13 was repeated, but using 1.32
g of
5-[4-(7-t-butyl-6-hydroxy-2-methyl-4-oxochroman-2-ylmethoxy)benzyl]thiazol
idine-2,4-dione (prepared as described in Example 24 of copending
U.S. Ser. No. 644,996), 2.0 g of hydroxylamine hydrochloride, 0.5
ml of pyridine and 20 ml of methanol, to give the title compound as
colorless crystals, melting at 235.degree.-237.degree. C. (with
decomposition).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO].delta.
ppm:
1.40 (12H, singlet);
2.6-4.0 (1H, broad, disappeared on adding heavy water);
2.98 (2H, singlet);
3.10 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.43 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.05 (2H, singlet);
4.74 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.73 (1H, singlet);
6.95 (2H, doublet, J=9 Hz);
7.2-8.5 (1H, broad, disappeared on adding heavy water);
7.25 (2H, doublet, J=9 Hz);
7.30 (1H, singlet);
9.7-10.6 (1H, broad, disappeared on adding heavy water).
EXAMPLE 21
5-{4-[6-Hydroxy-4-(E)-hydroxyimino-2-methyl-7-(1,1,3,3-tetramethylbutyl)chr
oman-2-ylmethoxy]benzyl)thiazolidine-2,4-dione
The procedure described in Example 13 was repeated, but using 1.0 g
of
5-{4-[6-hydroxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman
-2-ylmethoxy]benzyl}thiazolidine-2,4-dione (prepared as described
in Example 7), 0.26 g of hydroxylamine hydrochloride, 0.3 g of
pyridine and 10 ml of methanol, to give the title compound as a
white powder, softening at 115.degree.-120.degree. C.
Nuclear Magnetic Resonance spectrum [(CD.sub.3).sub.2 CO]
.delta.ppm:
0.76 (9H, singlet);
1.40 (9H, singlet);
2.00 (2H, singlet);
2.5-3.6 (1H, broad, disappeared on adding heavy water);
2.98 (2H, singlet);
3.09 (1H, doublet of doublets, J=9 .delta. 15 Hz);
3.44 (1H, doublet of doublets, J=4 .delta. 15 Hz);
4.03 (2H, singlet);
4.76 (1H, doublet of doublets, J=4 .delta. 0 Hz);
6.75 (1H, singlet);
6.93 (2H, doublet, J=9 Hz);
7.22 (2H, doublet, J=9 Hz);
7.25 (1H, singlet);
7.5-8.4 (1H, broad, disappeared on adding heavy water).
EXAMPLE 22
5-{4-[6-Hydroxy-4-(E)-hydroxyimino-2-isobutyl-5,7,8-trimethylchroman-b
2-ylmethoxy]benzyl}thiazolidine-2,4-dione
The procedure described in Example 13 was repeated, but using 155
mg of
5-[4-(6-hydroxy-2-isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)
benzyl]thiazolidine-2,4-dione (prepared as described in Example 1),
600 mg of hydroxylamine hydrochloride, 4 ml of ethanol and 6 ml of
pyridine, to give the title compound, softening at
77.degree.-80.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO]
.delta.ppm:
0.97 (6H, doublet, J=6 Hz);
1.6-2.3 (1H, nd);
1.78 (2H, doublet, J=6 Hz);
2.11 (3H, singlet);
2.18 (3H, singlet);
2.46 (3H, singlet);
2.7-3.7 (1H, broad, disappeared on adding heavy water);
2.8-3.2 (1H, nd);
3.09 (2H, singlet);
3.43 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.05 (2H, AB type, J=10 Hz);
4.72 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.91 (2H, doublet, J=9 Hz);
7.22 (2H, doublet, J=9 Hz);
9.8-10.5 (1H, broad singlet, disappeared on adding heavy
water).
EXAMPLE 23
5-{4-[2-(3,7-Dimethyloctyl)-6-hydroxy-4-(E)-hydroxyimino-5,7,8-trimethylchr
oman-2-trimethylchroman-2ylmethoxy]benzyl}thiazolidine-2,4-dione
The procedure described in Example 13 was repeated, but using 150
mg of
5-{4-[2-(3,7-dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-4-oxochroman
-2-ylmethoxy]benzyl}thiazolidine-2,4-dione (prepared as described
in Example 8), 36 mg of hydroxylamine hydrochloride, 41 mg of
pyridine and 2 ml of methanol, to give the title compound as a
slightly yellow powder, softening at 55.degree.-60 .degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.83 (9H, doublet, J=7 Hz);
1.0-2.0 (12H, multiplet);
2.10 (3H, singlet);
2.18 (3H, singlet);
2.41 (3H, singlet);
2.9-3.2 (1H, nd);
2.92 (1H, doublet, J=17 Hz);
3.2-3.55 (1H, nd);
3.23 (1H, doublet, J=17 Hz);
3.94 (2H, singlet);
4.3-4.8 (1H, nd);
4.46 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.83 (2H, doublet, J=9 Hz);
7.15 (2H, doublet, J=9 Hz);
7.8-8.9 (2H, broad, disappeared on adding heavy water).
EXAMPLE 24
5-[4-(6-Hydroxy-2,5,7,8-tetramethyl-4-(E)-methoxyiminochroman-2-ylmethoxy)b
enzyl]thiazolidine -2,4dione
A mixture of 1 g of
5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazo
lidine-2,4-dione (prepared as described in Example 22 of copending
U.S. Ser. No. 644,996), 0.6 g of methoxyamine hydrochloride and 5 g
of methanol was allowed to stand for 10 days at room temperature.
At the end of this time, ethyl acetate and an aqueous solution of
potassium carbonate were added. The organic layer was separated and
dried over anhydrous sodium sulfate. The solvent was distilled off
and the residue was purified by silica gel column chromatography
eluted with a 3:1 by volume mixture of hexane and ethyl acetate, to
give the title compound softening at 72.degree.-76.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.41 (3H, singlet);
2.08 (3H, singlet);
2.17 (3H, singlet);
2.50 (3H, singlet);
2.88 .delta. 3.08 (2H, AB type, J=17 Hz);
3.00 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.42 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.92 (2H, singlet);
3.96 (3H, singlet);
4.2-4.9 (1broad);
4.45 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.83 (2H, doublet, J=9 Hz);
7.12 (2H, doublet, J=9 Hz).
EXAMPLE 25
5-{4-[4-(E)-Benzyloxyimino-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy
]benzyl}thiazolidine-2,4-dione
A mixture of 1 g of
5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazo
lidine-2,4-dione (prepared as described in Example 22 of copending
U.S. Ser. No. 644,996), 1.2 g of benzyloxylamine hydrochloride and
10 g of methanol was allowed to stand for 7 days at room
temperature. At the end of this time, ethyl acetate and an aqueous
solution of potassium carbonate were added. The organic layer was
separated and dried over anhydrous sodium sulfate. The solvent was
distilled off and the residue was purified by silica gel column
chromatography eluted with a 3:1 by volume mixture of hexane and
ethyl acetate, to give the title compound, softening at
64.degree.-69.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.40 (3H, singlet);
2.06 (3H, singlet);
2.16 (3H, singlet);
2.41 (3H, singlet);
2.92 .delta. 3.18 (2H, AB type, J=17 Hz);
3.02 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.42 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.90 (2H, singlet);
4.43 (b 1H, doublet of doublets, J=4 .delta. 9 Hz);
5.19 (2H, singlet);
6.82 (2H, doublet, J=9 Hz);
7.11 (2H, doublet, J=9 Hz);
7.2-7.5 (5H, multiplet).
EXAMPLE 26
5-{4-84-(E)-t-Butoxycarbonylmethoxyimino-6-hydroxy-2,5,7,8-tetramethylchrom
an-2-ylmethoxy]benzyl }thiazolidine-2,4-dione
A mixture of 1 g of
5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazo
lidine-2,4-dione (prepared as described in Example 22 of copending
U.S. Ser. No. 644,996), 2.1 g of t-butoxycarbonylmethoxylammonium
p-toluenesulfonate, 5 g of methanol and 0.6 g of pyridine was
allowed to stand for 7 days at room temperature. At the end of this
time, ethyl acetate and an aqueous solution of potassium carbonate
were added. The organic layer was separated and dried over
anhydrous sodium sulfate. The solvent was distilled off and the
residue was purified by silica gel column chromatography eluted
with a 3:1 by volume mixture of hexane and ethyl acetate, to give
the title compound, softening at 76.degree.-80.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.44 (3H, singlet);
1.49 (9H, singlet);
2.07 (3H, singlet);
2.17 (3H, singlet);
2.43 (3H, singlet);
3.02 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.08 (2H, AB type, J=17 Hz);
3.42 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.96 (2H, singlet);
4.43 (1H, doublet of doublets, J=4 .delta. 9 Hz);
4.57 (2H, singlet);
4.9-6.1 (2H, broad, disappeared on adding heavy water);
6.84 (2H, doublet, J=9 Hz);
7.10 (2H, doublet, J=9 Hz).
EXAMPLE 27
(a)
5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2yl-methoxy)benzyl]-2-iminothia
zolidin-4-one and (b)
5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine
-2,4-dione (Step A5)
A mixture of 9.6 g of ethyl
3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropro
pionate (prepared as described in Preparation 51), 1.8 g of
thiourea and 11 ml of sulfolane was heated at
115.degree.-120.degree. C. for 80 minutes under a stream of
nitrogen. A mixture of 90 ml of acetic acid, 30 ml of concentrated
hydrochloric acid and 15 ml of water was then added to the reaction
mixture, which was then heated at 85.degree.-90.degree. C. for a
further 12 hours. 27 g of sodium bicarbonate were added to the
reaction mixture, and, after the generation of carbon dioxide gas
had ceased, the solvent was distilled off. A mixture of 10 parts by
volume of benzene and 1 part of ethyl acetate was added to the
crude residue, and the resulting solution was washed with a 1:1 by
volume mixture of a saturated aqueous solution of sodium
bicarbonate and water. A white powdery product was collected by
filtration, washed with water and recrystallized from acetone to
give the title compound (a), melting at 205.degree.-207.degree.
C.
Nuclear Magnetic Resonance Spectrum [DCON(CD.sub.3).sub.2 +D.sub.2
O] .delta. ppm:
1.37 (3H, singlet);
about 2 (2H, multiplet);
2.02 (3H, singlet);
2.14 (6H, singlet);
2.3-3.1 (adsorption signal of solvent);
3.42 (1H, doublet of doublets, J=15 .delta. 4.5 Hz);
4.60 (1H, doublet of doublets , J=9 .delta. 4.5 Hz);
6.93 (2H, doublet, J=9 Hz);
7.23 (2H, doublet, J=9 Hz).
The organic layer which was obtained after removal of the above
white powder was washed with water and dried over anhydrous sodium
sulfate. The solvent was distilled off and the resulting crude
residue was purified by silica gel column chromatography. After
elution with a 10:1 by volume mixture of benzene and ethyl acetate,
the title compound (b) was obtained as a powder, melting at
184.degree.-186.degree. C., from the next elution with a 10:1.4 by
volume mixture of benzene and ethyl acetate.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO] .delta.
ppm:
1.39 (3H, singlet);
about 2 (2H, multiplet);
2.02 (3H, singlet);
2.09 (3H, singlet);
2.13 (3H, singlet);
2.63 (2H, broad triplet, J=6 Hz);
3.07 (1H, doublet of doublets, J=15 .delta. 9 Hz);
3.41 (1H, doublet of doublets, J=15 .delta. 4.5 Hz);
3.97 (2H, AB type, J=9 Hz);
4.70 (2H, doublet of doublets, J=9 .delta. 4.5 Hz);
6.90 (2H, doublet, J=9 Hz);
7.21 (2H, doublet, J=9 Hz).
EXAMPLE 28
5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-
2,4-dione (Step A5)
A mixture of 9.6 g of ethyl
3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropro
pionate (prepared as described in Preparation 51), 1.8 g of
thiourea and 11 ml of sulfolane was heated for 3.5 hours at
120.degree. C. under a nitrogen stream. 100 ml of ethylene glycol
monomethyl ether and 70 ml of 10% w/v aqueous hydrochloric acid
were then added to the reaction mixture, after which it was heated
under reflux for 12 hours. The product was then purified as
described in Example 27, to give the title compound. The melting
point and nuclear magnetic resonance spectrum of this compound
accorded with those of the compound obtained in Example 27(b).
EXAMPLE 29
5-[4-(7-t-Butyl-6-hydroxy-2-methylchroman-2-ylmethoxy)benzyl]thiazolidine-2
,4-dione (Step A5)
Following the procedure described in Example 28, a mixture of 1.43
g of ethyl
3-[4-(6-acetoxy-8-t-butyl-2-methylchroman-2-ylmethoxy)phenyl]-2-chloroprop
ionate (prepared as described in Preparation 59), 430 mg of
thiourea and 5 ml of sulfolane was heated for 3.5 hours at
120.degree. C. 15 ml of ethylene glycol monomethyl ether and 10 ml
of 10% w/v aqueous hydrochloric acid were then added to the
reaction mixture, after which it was heated under reflux for 13
hours. The product was then separated and purified as described in
Example 27, to give the title compound as a slightly yellow
powder.
Rf value on silica gel thin layer chromatography=0.31 (developing
solvent, benzene:ethyl acetate=5:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.37 (9H, singlet);
1.43 (3H, singlet);
1.63-2.30 (2H, multiplet);
2.67 (2H, broad triplet, J=7 Hz);
3.07 (1H, doublet of doublets, J=9 .delta. 15 Hz);
3.45 (1H, doublet of doublets, J=4 .delta. 15 Hz);
3.87 .delta. 3.97 (2H, AB type, J=9 Hz);
4.48 (1H, doublet of doublets, J=4 .delta. 9 Hz);
4.62 (1H, broad singlet, disappeared on adding heavy water);
6.41 (1H, singlet);
6.78 (1H, singlet);
6.88 (2H, doublet, J=9 Hz);
7.15 (2H, doublet, J=9 Hz);
8.40-8.93 (1H, broad, disappeared on adding heavy water).
5-[4-(4,6-Dihydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl]thiazoli
dine-2,4-dione (Step H1)
450 mg of sodium borohydride were added to a mixture of 278 mg of
5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazo
lidine -2,4-dione (prepared as described in Example 22 of copending
U.S. Ser. No. 644,996) and 9 ml of methanol, and the mixture was
stirred for 2 hours at room temperature, after which a 1% w/v
aqueous solution of acetic acid was added and the mixture was
neutralized with an aqueous solution of potassium carbonate. It was
then extracted with ethyl acetate. The ethyl acetate extract was
washed with water and dried over anhydrous sodium sulfate. The
ethyl acetate was distilled from the extract under reduced pressure
and the resulting residue was purified by silica gel column
chromatography, using a 5:3 by volume mixture of hexane and ethyl
acetate as eluent, to give the title compound, melting at
102.degree.-118.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO+D.sub.2 O]
.delta. ppm:
1.52 (3H, singlet);
2.01 (3H, singlet);
2.13 (3H, singlet: 2.29 (3H, singlet);
1.9-2.5 (1H, nd);
2.9-3.6 (2H, multiplet);
4.03 (2H, singlet);
3.9-4.5 (1H, nd);
4.6-5.1 (2H, multiplet);
6.7-7.4 (4H, nd).
EXAMPLE 31
(a)
2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethylch
roman-6-yl hydrogen succinate
A mixture of 1.0 g of
5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine
-2,4-dione (prepared as described in Example 28), 0.31 g of
succinic anhydride and 1 ml of pyridine was allowed to stand
overnight at room temperature. The reaction mixture was then washed
3 times, each time with 10 ml of cyclohexane, and the insoluble
residue obtained was purified by silica gel column chromatography
(eluted by mixtures of benzene and ethyl acetate ranging from 5:1
to 1:1) to give the title compound melting at
197.degree.-202.degree. C.
Nuclear Magnetic Resonance Spectrum (pentadeuterated pyridine)
.delta. ppm:
1.36 (3H, singlet);
1.5-2.3 (2H, multiplet);
2.10 (6H, singlet);
2.14 (3H, singlet);
2.5 (2H, broad triplet, J=6 Hz);
2.7-3.35 (5H, multiplet;
3.60 (1H, doublet of doublets, J=4 .delta. 15 Hz);
3.95 .delta. 4.05 (2H, AB-type, J=9 Hz);
4.90 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.98 (2H, doublet, J=9 Hz);
7.30 (2H, doublet, J=9 Hz).
(b)
2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetramethylch
roman-6-yl hydrogen succinate sodium salt
1 ml of a 2.5% w/v methanolic solution of sodium methoxide was
added to a suspension of 246 mg of the compound obtained as
described in (a) above in 100 ml of methanol at room temperature.
Insoluble matter was filtered off, and then the methanol was
distilled off under reduced pressure and the residue was washed
with diethyl ether to give the title compound, melting at
178.degree.-180.degree. C.
EXAMPLE 32
5-[4-(6-Hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-yl-methoxy)benzyl]thiazoli
dine-2,4-dione
A mixture of 140 mg of
5-[4-(4,6-dihydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazoli
dine-2,4-dione (prepared as described in Example 30), 10 mg of
p-toluenesulfonic acid, 10 ml of benzene and 0.5 ml of
dimethylformamide was heated under reflux for 1 hour. The reaction
solution was cooled, washed with a saturated aqueous solution of
sodium bicarbonate and then with water and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure and the residue was purified by silica gel column
chromatography eluted with a 4:1 by volume mixture of benzene and
ethyl acetate, to give the title compound, softening at
173.degree.-176.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO]
.delta.ppm:
1.50 (3H, singlet);
2.02 (3H, singlet);
2.12 (3H, singlet);
2.18 (3H, singlet);
3.06 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.40 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.94 (1H, doublet, J=10 Hz);
4.05 (1H, doublet, J=10 Hz);
4.70 (1H, doublet of doublets, J=4 .delta. 9 Hz);
5.75 (1H, doublet, J=10 Hz);
6.72 (1H, doublet, J=10 Hz);
6.85 (2H, doublet, J=9 Hz);
7.19 (2H, doublet, J=9 Hz).
EXAMPLE 33
5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-
2,4-dione (Step H3)
Following the procedure described in Preparation 58, 120 mg of
5-[4-(6-hydroxy-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy)benzyl]thiazoli
dine -2,4-dione (prepared as described in Example 32) were
dissolved in 4 ml of methanol and, in the presence of 40 mg of 10%
w/w palladium-on-carbon, it was reduced under 3-5 atmospheres
(about 3-5 bars) pressure of hydrogen, to give the title compound.
The melting point and nuclear magnetic resonance spectrum of this
compound accorded with those of the compound obtained in Example
27(b).
EXAMPLE 34
5-[4-(4-Carboxymethoxyimino-6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethox
y)benzyl]thiazolidine -2,4-dione
A mixture of 0.7 g of
5-[4-(4-t-butoxycarbonylmethoxyimino-6-hydroxy-2,5,7,8-tetramethylchroman
-2ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in
Example 26) and 7 ml of a 4N dioxane solution of hydrogen chloride
was allowed to stand at room temperature for 15 hours. At the end
of this time, the solvent was distilled off and the residue was
washed with warm water to give the title compound, softening at
75.degree.-85.degree. C.
Nuclear Magnetic Resonance Spectrum ](CD.sub.3).sub.2 SO].delta.
ppm:
1.33 (3H, singlet);
1.98 (3H, singlet);
2.09 (3H, singlet);
2.34 (3H, singlet);
2.9-3.5 (2H, multiplet);
3.0 (2H, singlet);
4.02 (2H, singlet);
4.65 (2H, singlet);
4.84 (1H, doublet of doublets, J=4 .delta.9 Hz);
6.90 (2H, doublet, J=9 Hz);
7.17 (2H, doublet, J=9 Hz);
7.55-7.95 (1H, broad, disappeared on adding heavy water).
EXAMPLE 35
2-Methoxyethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetr
amethyl -4-oxochroman-6-yloxy}acetate
A mixture of 13 g of ethyl
3-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmetho
xy)phenyl]-2-chloropropionate (prepared as described in Preparation
64), 2.6 g of thiourea and 15 ml of sulfolane was heated under a
nitrogen stream at 120.degree.-130.degree. C. for 5 hours. 30 ml of
2N aqueous hydrochloric acid and 60 ml of 2-methoxyethanol were
added to the resulting mixture, which was then heated at
110.degree. C. for 3 hours. The reaction mixture was then poured
into water and extracted with ethyl acetate. The extract was washed
with water and dried over anhydrous sodium sulfate. The solvent was
distilled from the dried extract, and the residue was purified by
silica gel column chromatography (eluted with a 4:1 by volume
mixture of benzene and ethyl acetate) to give the title
compound.
Rf value on silica gel thin layer chromatography=0.14 (developing
solvent, benzene:ethyl acetate=4:1 by volume).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.50 (3H, singlet);
2.10 (3H, singlet);
2.26 (3H, singlet);
2.45-2.8 (1H, nd);
2.56 (3H, singlet);
2.9-3.25 (1H, nd);
3.07 (1H, doublet, J=16 Hz);
3.40 (3H, singlet);
3.4-3.6 (1H, nd);
3.6-3.75 (2H, multiplet);
3.98 .delta. 4.11 (2H, AB type, J=10 Hz);
4.3-4.45 (2H, multiplet);
4.34 (2H, singlet);
4.45-4.6 (1H, nd);
6.85 (2H, doublet, J=9 Hz);
7.16 (2H, doublet, J=9 Hz);
8.7-9.3 (1H, broad).
EXAMPLE 36
5-[4-(6-Ethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-2
,4-dione
The title compound, melting at 56.degree.-60.degree. C., was
obtained from 5.1 g of ethyl
2-chloro-3-[4-(6-ethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]prop
ionate (prepared as described in Preparation 65), 1 g of thiourea,
6 ml of sulfolane, 16 ml of 2N aqueous hydrochloric acid and 5 ml
of 2-methoxyethanol, according to the same procedure as described
in Example 35.
Mass spectrum (m/e): 469 (M.sup.+).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.39 (3H, triplet, J=7 Hz);
1.41 (3H, singlet);
1.7-2.1 (2H, nd);
2.07 (3H, singlet);
2.14 (3H, singlet);
2.17 (3H, singlet);
2.61 (2H, broad triplet, J=7 Hz);
3.05 (1H, doublet of doublets, J=10 .delta. 14 Hz);
3.45 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.72 (2H, quartet, J=7 Hz);
3.87 .delta. 3.97 (2H, AB type, J=9 Hz);
4.47 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.87 (2H, doublet, J=9 Hz);
7.14 (2H, doublet, J=9 Hz);
8.6-8.8 (1H, broad, disappeared on adding heavy water).
EXAMPLE 37
2-Methoxyethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-4-hydroxy
-2,5,7,8-tetramethylchroman-6-yloxy}acetate
1.5 g of sodium borohydride were added, whilst ice-cooling, to a
mixture of 1.2 g of 2-methoxyethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)-phenoxymethyl]-2,5,7,8-tet
ramethyl-4-oxochroman -6-yloxy}acetate (prepared as described in
Example 35) and 20 ml of methanol, and the mixture was stirred for
60 minutes. The reaction mixture was then poured into ice-water,
neutralized with 10% w/v aqueous hydrochloric acid, and then
extracted with ethyl acetate. The extract was washed with water and
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure to give the title compound as a pale yellow
powder.
Rf value on silica gel thin layer chromatography=0.20 (developing
solvent, benzene:ethyl acetate=1:1 by volume).
Mass spectrum (m/e) : 573 (M.sup.+).
EXAMPLE 38
Methyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetr
amethyl-2H-chromen -6-yloxy}acetate
A mixture of 970 mg of 2-methoxyethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]4-hydroxy-2,5
,7,8-tetramethylchroman-6-yloxy}acetate (prepared as described in
Example 37), 50 mg of p-toluenesulfonic acid, 10 ml of benzene and
1 ml of dioxane was heated under reflux in a nitrogen stream for 60
minutes. The reaction mixture was then washed with a 5% w/v aqueous
solution of sodium bicarbonate and then with water, and dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure. The residue was purified by silica gel column
chromatography (eluted with a 7:3 by volume mixture of benzene and
ethyl acetate), to give the title compound.
Rf value on silica gel thin layer chromatography=0.74 (developing
solvent, benzene:ethyl acetate=1:1 by volume).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO].delta.
ppm:
1.51 (3H, singlet);
2.01 (3H, singlet);
2.14 (3H, singlet);
2.22 (3H, singlet);
3.07 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.42 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.74 (3H, singlet);
4.03 (2H, singlet);
4.32 (2H, singlet);
4.73 (1H, doublet of doublets, J=4 .delta. 9 Hz);
5.80 (1H, doublet, J=10 Hz);
6.70 (1H, doublet, J=10 Hz);
6.86 (2H, doublet, J=9 Hz);
7.20 (2H, doublet, J=9 Hz).
EXAMPLE 39
2-Methoxyethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetr
amethyl -2H-chromen-6-yloxy}acetate
The title compound was obtained from the fraction eluted after the
one giving the methyl ester in the column chromatography described
in Example 38, using the same eluent.
Rf value on silica gel thin layer chromatography=0.59 (developing
solvent, benzene;ethyl acetate=1:1 by volume).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO].delta.
ppm:
1.52 (3H, singlet);
2.02 (3H, singlet);
2.16 (3H, singlet);
2.23 (3H, singlet);
3.09 (1H, doublet of doublets, J=9 .delta. 15 Hz);
3.30-3.60 (1H, nd);
3.32 (3H, singlet);
3.5-3.7 (2H, multiplet);
4.04 (2H, singlet);
4.25-4.45 (2H, multiplet);
4.35 (2H, singlet);
4.75 (1H, doublet of doublets, J=4 .delta. 9 Hz);
5.82 (1H, doublet, J=10 Hz);
6.72 (1H, doublet, J=10 Hz);
6.88 (2H, doublet, J=9 Hz);
7.21 (2H, doublet, J=9 Hz).
EXAMPLE 40
5-{4-[6-(2-Hydroxyethoxy)-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy]benzyl
}thiazolidine-2,4-dione
The title compound was obtained from the fraction eluted after the
one giving the 2-methoxyethyl ester in the silica gel column
chromatography described in Example 39, using the same eluent.
Rf value on silica gel thin layer chromatography=0.44 (developing
solvent, benzene:ethyl acetate=1:1 by volume).
Nuclear magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO].delta.
ppm:
1.51 (3H, singlet);
2.01 (3H, singlet);
2.15 (3H, singlet);
2.21 (3H, singlet);
3.08 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.42 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.6-3.95 (4H, multiplet);
4.03 (2H, singlet);
4.74 (1H, doublet of doublets, J=4 .delta. 9 Hz);
5.78 (1H, doublet, J=10 Hz);
6.71 (1H, doublet, J=10 Hz);
6.88 (2H, doublet, J=9 Hz);
7.21 (2H, doublet, J=9 Hz).
EXAMPLE 41
2-Methoxyethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetr
amethylchroman-6-yloxy}acetate
Using Paar's hydrogenation apparatus, a mixture of 260 mg of
2-methoxyethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetr
amethyl-2H-chromen-6-yloxy}acetate (prepared as described in
Example 39), 300 mg of 10% w/v palladium-on-carbon and 50 ml of
ethanol was stirred for 10 hours under a hydrogen pressure of 3-5
atmospheres. The palladium-on-carbon was then filtered off, and the
filtrate was condensed by evaporation under reduced pressure, to
give the title compound as a colorless oily substance.
Rf value on silica gel thin layer chromatography=0.34 (developing
solvent, benzene:ethyl acetate=2.1 by volume).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.40 (3H, singlet);
1.75-2.15 (2H, nd);
2.06 (3H, singlet);
2.14 (3H, singlet);
2.18 (3H, singlet);
2.61 (2H, broad triplet, J=7 Hz);
3.05 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.35-3.8 (3H, nd);
3.39 (3H, singlet);
3.86 .delta. 3.96 (2H, AB type, J=10 Hz);
4.25-4.6 (3H, nd);
4.34 (2H, singlet);
6.87 (2H, doublet, J=9 Hz);
7.15 (2H, doublet, J=9 Hz);
8.35-8.8 (1H, broad, disappeared on adding heavy water).
EXAMPLE 42
5-{4-[6-(2-Hydroxyethoxy)-2,5,7,8-tetramethylchroman-2-ylmethoxy]benzyl}thi
azolidine -2,4dione
Following the same procedure as described in Example 41, 0.35 g of
5-{4-[6-(2-hydroxyethoxy)-2,5,7,8-tetramethyl-2H-chromen-2-ylmethoxy]benzy
l}-thiazolidine-2,4-dione (prepared as described in Example 40),
0.3 g of 10% w/w palladium on activated carbon and 10 ml of ethanol
gave the title compound.
Rf value on silica gel thin layer chromatography=0.45 (developing
solvent, benzene:ethyl acetate=1:1 by volume).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.41 (3H, singlet);
1.7-2.2 (2H, nd);
2.07 (3H, singlet);
2.13 (3H, singlet);
2.18 (3H, singlet);
2.61 (2H, broad triplet, J=7 Hz);
3.05 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.44 (1H, doublet of doublets, J=5 .delta. 14 Hz);
3.7-4.1 (6H, multiplet);
4.47 (1H, doublet of doublets, J=4 .delta. 9 Hz);
4.8-5.2 (2H, broad);
6.87 (2H, doublet, J=9 Hz);
7.14 (2H, doublet, J=9 Hz).
EXAMPLE 43
Ethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetr
amethyl-4-oxochroman-6-yloxy}acetate
A mixture of 0.5 g of
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetr
amethyl-4-oxo-chroman-6-yloxy}acetic acid (obtained as described in
Example 59), 0.5 ml of a 4N dioxane solution of hydrogen chloride
and 5 ml of ethanol was allowed to stand overnight at room
temperature. The reaction mixture was then poured into water and
the solution was neutralized with sodium bicarbonate and extracted
with ethyl acetate. The extract was washed with water and dried
over anhydrous sodium sulfate. The solvent was distilled off, and
the residue was subjected to preparative silica gel thin layer
chromatography (developing solvent, benzene:ethyl acetate=7:3 by
volume) to obtain the title compound.
Rf value on silica gel thin layer chromatography=0.70 (developing
solvent, benzene:ethyl acetate=1:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.33 (3H, triplet, J=7 Hz);
1.50 (3H, singlet);
2.10 (3H, singlet);
2.26 (3H, singlet);
2.57 (3H, singlet);
2.55-2.8 (1H, nd);
3.06 (1H, doublet, J=16 Hz);
3.07 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.45 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.00 .delta. 4.11 (2H, AB type, J=10 Hz);
4.29 (2H, singlet);
4.31 (2H, quartet, J=7 Hz);
4.48 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.85 (2H, doublet, J=9 Hz);
7.16 (2H, doublet, J=9 Hz);
8.3-8.9 (1H, broad).
EXAMPLE 44
t-Butyl
.alpha.-{5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,
4-dioxothiazolidin-3yl}acetate
0.87 g of t-butyl bromoacetate was added dropwise, whilst
ice-cooling, to a mixture of 1 g of
5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl
]thiazolidine-2,4-dione [prepared as described in Example 3(b) of
copending U.S. Ser. No. 644,996], 0.43 g of anhydrous potassium
carbonate, and 8 ml of acetone. The resulting mixture was stirred
for 2 hours at room temperature and then allowed to stand for 2
days, also at room temperature. The reaction mixture was then
poured into ice-water and extracted with ethyl acetate. The extract
was washed with a saturated aqueous solution of sodium chloride and
dried over anhydrous sodium sulfate. The solvent was distilled off
and the residue was subjected to silica gel column chromatography
(eluent:benzene) to give the title compound.
Rf value on silica gel thin layer chromatography=0.6 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.41 (3H, singlet);
1.47 (9H, singlet);
1.7-2.1 (2H, nd);
1.98 (3H, singlet);
2.02 (3H, singlet);
2.07 (3H, singlet);
2.30 (3H, singlet);
2.62 (2H, broad triplet, J=7 Hz);
2.98 (1H, doublet of doublets, J=10 .delta. 14 Hz);
3.55 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.86 .delta. 3.97 (2H, AB type, J=9 Hz);
4.19 (2H, singlet);
4.45 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.86 (2H, doublet J=9 Hz);
7.15 (2H, doublet, J=9 Hz).
EXAMPLE 45
Methyl
.alpha.-{5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,
4-dioxothiazolidin -3-yl}acetate
Following the procedure described in Example 44, 2.4 g of
5-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine
-2,4-dione [prepared as described in Example 3(b) of copending U.S.
Ser. No. 644,996], 1.5 g of methyl bromoacetate, 1.5 g of potassium
carbonate and 25 ml of acetone gave the title compound as a
colourless oil.
Rf value on silica gel thin layer chromatography=0.26 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.42 (3H, singlet);
1.8-2.25 (2H, nd);
1.98 (3H, singlet);
2.02 (3H, singlet);
2.08 (3H, singlet);
2.30 (3H, singlet);
2.64 (2H, broad triplet, J=7 Hz);
3.01 (1H, doublet of doublets, J=10 .delta. 14 Hz);
3.54 (1H, doublet of doublets, J=4.5 .delta. 14 Hz);
3.75 (3H, singlet);
3.87 .delta. 4.00 (2H, AB type, J=9 Hz);
4.31 (2H, singlet);
4.50 (1H, doublet of doublets, J=4.5 .delta. 10 Hz);
6.89 (2H, doublet, J=9 Hz);
7.17 (2H, doublet, J=9 Hz).
EXAMPLE 46
t-butyl
.alpha.-{5-[4-(6hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4
-dioxothiazolidin -3-yl}acetate
Following the procedure described in Example 44, 1 g of
5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine
-2,4-dione [prepared as described in Example 27(b)], 0.47 g of
anhydrous potassium carbonate, 0.93 g of t-butyl bromoacetate and 8
ml of acetone gave the title compound.
Rf value on silica gel thin layer chromatography=0.52 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.42 (3H, singlet);
1.48 (9H, singlet);
1.7-2.15 (2H, nd);
2.11 (6H, singlet);
2.16 (3H, singlet);
2.64 (2H, broad triplet, J=7 Hz);
2.99 (1H, doublet of doublets, J=10 .delta. 14 Hz);
3.56 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.85 .delta. 3.98 (2H, AB type, J=9 Hz);
4.21 (2H, singlet);
4.24 (1H, singlet);
4.46 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.88 (2H, doublet, J=9 Hz);
7.15 (2H, doublet, J=9 Hz).
EXAMPLE 47
Di-t-butyl
.alpha.,.alpha.'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchrom
an-2-ylmethoxy)benzyl
]-2,4-dioxothiazolidine-3,5-diyl}diacetate
1.9 g of t-butyl bromoacetate was added dropwise, whilst
ice-cooling, to a mixture of 1 g of
5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine
-2,4-dione [prepared as described in Example 27(b)], 0.94 g of
anhydrous potassium carbonate and 10 ml of acetone. The resulting
mixture was stirred for 2 days at room temperature. The reaction
mixture was then poured into ice-water and extracted with benzene.
The extract was washed with water and dried over anhydrous sodium
sulfate. The solvent was distilled off and the residue was
subjected to silica gel column chromatography (eluent,
benzene:ethyl acetate =20:1 by volume) to give the title
compound.
Rf value on silica gel thin layer chromatography=0.54 (developing
solvent, cyclohexane:ethyl acetate=4:1 by volume).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3 .delta. ppm:
1.44 (9H, singlet);
1.48 (12H, singlet);
1.54 (9H, singlet);
1.8-2.1 (2H, nd);
2.07 (3H, singlet);
2.16 (3H, singlet);
2.20 (3H, singlet);
2.5-2.7 (2H, multiplet);
2.9-3.15 (2H, multiplet);
3.24 (2H, singlet);
3.93 (2H, broad singlet);
4.13 (2H, singlet);
4.17 (2H, singlet);
6.85 (2H, broad doublet, J=9 Hz);
7.15 (2H, broad doublet, J=9 Hz).
Mass Spectrum (m/e) : 783 (M.sup.+).
EXAMPLE 48
t-Butyl-.alpha.-{55-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroma
n-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate
In the column chromatography separation process described in
Example 47, the title compound was obtained from the fractions
eluted after those giving the t-butyl ester of Example 47, using
the same eluent.
Rf value on silica gel thin layer chromatography=0.42 (developing
solvent, cyclohexane:ethyl acetate=4:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.42 (3H, singlet);
1.48 (9H, singlet);
1.54 (9H, singlet);
1.7-2.1 (2H, nd);
2.06 (3H, singlet);
2.15 (3H, singlet);
2.19 (3H, singlet);
2.61 (2H, broad triplet, J=7 Hz);
2.99 (1H, doublet of doublets, J=10 .delta. 14 Hz);
3.56 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.87 .delta. 3.96 (2H, AB type, J=9 Hz);
4.17 (2H, singlet);
4.20 (2H, singlet);
4.46 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.87 (2H, doublet, J=9 Hz);
7.15 (2H, doublet, J=9 Hz).
Mass Spectrum (m/e) : 669 (M.sup.+).
EXAMPLE 49
t-Butyl
.alpha.-{5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benz
yl]-2,4-dioxothiazolidin-3-yl}acetate
Following the procedure described in Example 44, 1 g of
5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazo
lidine-2,4-dione (prepared as described in Example 22 of copending
U.S. Ser. No. 644,996), 0.45 g of anhydrous potassium carbonate,
0.9 g of t-butyl bromoacetate and 8 ml of acetone gave the title
compound, softening at 170.degree.-180.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO].delta.
ppm:
1.46 (9H, singlet);
1.50 (3H, singlet);
2.10 (3H, singlet);
2.22 (3H, singlet);
2.5-2.8 (1H, nd);
2.54 (3H, singlet);
3.03 (1H, doublet of doublets, J=10 .delta. 14 Hz);
3.04 (1H, doublet, J=16 Hz);
3.53 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.16 (2H, singlet);
4.22 (2H, singlet);
4.82 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.96 (2H, doublet, J=9 Hz);
7.25 (2H, doublet, J=9 Hz).
EXAMPLE 50
Di-t-butyl
.alpha.,.alpha.'{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxo
chroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate
Following the procedure described in Example 47, 1.5 g of
5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazo
lidine-2,4-dione (prepared as described in Example 22 of copending
U.S. Ser. No. 644,996), 1.3 g of anhydrous potassium carbonate, 5.4
g of t-butyl bromoacetate and 10 ml of acetone gave the title
compound.
Rf value on silica gel thin layer chromatography=0.57 (developing
solvent, cyclohexane:ethyl acetate=7:3 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.42 (9H, singlet);
1.46 (9H, singlet);
1.48 (3H, singlet);
1.52 (9H, singlet);
2.10 (3H, singlet);
2.26 (3H, singlet);
2.55-3.20 (4H, nd);
2.56 (3H, singlet);
3.23 (2H, singlet);
3.97 .delta. 4.08 (2H, AB type, J=10 Hz);
4.12 (2H, singlet);
4.16 (2H, singlet);
6.82 (2H, doublet, J=9 Hz);
7.15 (2H, doublet, J=9 Hz).
Mass spectrum (m/e): 797 (M.sup.+).
EXAMPLE 51
t-Butyl
.alpha.-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-
2-ylmethoxy)benzyl ]-2,4-dioxothiazolidin-3-yl}acetate
From the fraction eluted following the one giving di-t-butyl
.alpha.,.alpha.'-{5-[4-(6-t-butyloxycarbonylmethoxy-2,5,7,8-tetramethyl-4-
oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate
as described in Example 50, the title compound was obtained, using
the same eluent.
Rf value on silica gel thin layer chromatography=0.46 (developing
solvent, cyclohexane:ethyl acetate=7:3 by volume).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.47 (9H, singlet);
1.50 (3H, singlet);
1.53 (9H, singlet);
2.10 (3H, singlet);
2.26 (3H, singlet);
2.56 (3H, singlet);
2.6-3.2 (3H, nd);
3.57 (1H, doublet of doublets, J=4 .delta. 14 Hz);
3.98 .delta. 4.11 (2H, AB type, J=10 Hz);
4.17 (2H, singlet);
4.20 (2H, singlet);
4.47 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.86 (2H, doublet, J=9 Hz);
7.16 (2H, doublet, J=9 Hz).
Mass spectrum (m/e): 683 (M.sup.+).
EXAMPLE 52
3-Ethyl-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiaz
olidine-2,4dione
Following the procedure described in Example 44, 0.58 g of
5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine
-2,4-dione [prepared as described in Example 27(b)], 0.27 g of
anhydrous potassium carbonate, 0.6 g of ethyl iodide and 5 ml of
acetone gave the title compound.
Rf value on silica gel thin layer chromatography=0.30 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.09 (3H, triplet, J=7 Hz);
1.40 (3H, singlet);
1.7-2.2 (2H, nd);
2.09 (6H, singlet);
2.14 (3,singlet);
2.62 (2H, broad triplet, J=7 Hz);
3.02 (1h, doublet of doublets, J=9 .delta. 14 Hz);
3.25-3.5 (1H, nd);
3.59 (2H, quartet, J=7 Hz);
3.83 .delta. 3.96 (2H, AB type, J=10 Hz);
4.23 (1H, singlet, disappeared on adding heavy water);
4.36 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.84 (2H, doublet, J=9 Hz);
7.11 (2H, doublet, J=9 Hz).
EXAMPLE 53
t-Butyl
.alpha.-{5-[4-(6-hydroxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmet
hoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate
A mixture of 0.5 g of t-butyl
.alpha.-{5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benz
yl]-2,4-dioxothiazolidin-3yl}acetate (prepared as described in
Example 49), 0.25 g of hydroxylamine hydrochloride, 0.25 g of
pyridine and 5 ml of methanol was allowed to stand t
25.degree.-30.degree. C. for 2 days. Ethyl acetate and an aqueous
solution of potassium carbonate were added to the mixture, and the
organic layer was separated. The organic layer was dried over
anhydrous sodium sulfate. The solvent was distilled off and the
residue was subjected to silica gel column chromatography (eluted
with a 9:1 by volume mixture of benzene and ethyl acetate) to
obtain the title compound.
Rf value on silica gel thin layer chromatography=0.55 (developing
solvent, benzene:ethyl acetate=4:1 by volume).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO].delta.
ppm:
1.42 (3H, singlet);
1.45 (9H, singlet);
2.07 (3H, singlet);
2.17 (3H, singlet);
2.46 (3H, singlet);
3.03 (1H, doublet of doublets, J=.delta. 13.5 Hz);
3.07 (2H, singlet);
3.55 (1H, doublet of doublets, J=4 .delta. 13.5 Hz);
4.06 (2H, singlet);
4.18 (2H, singlet);
4.83 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.94 (2H, doublet, J=9 Hz);
7.25 (2H, doublet, J=9 Hz);
10.2 (1H, broad singlet, disappeared adding heavy water).
EXAMPLE 54
2-Methoxyethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl-4-hydroxyimin
o -2,5,7,8-tetramethylchroman-6-yloxy}acetate
A mixture of 0.6 g of 2-methoxyethyl
.alpha.-{2-[49(2,4-dioxothiazolidin-5-oxochroman-6-yloxy {acetate
(prepared as described in Example 35), 0.3 g of hydroxylamine
hydrochloride, 0.3 g of pyridine and 6 ml of methanol was allowed
to stand at 25.degree.-30 .degree. C. for 2 days. Ethyl acetate and
an aqueous solution of potassium carbonate were added to the
mixture, and the organic layer was separated. The organic layer was
dried over anhydrous sodium sulfate. The solvent was distilled off
and the residue was subjected to silica gel column chromatography
(eluted with a 7:3 by volume mixture of benzene and ethyl acetate)
to obtain the title compound.
Rf value on silica gel thin layer chromatography=0.32 (tailing)
(developing solvent, benzene:ethyl acetate=3:2 by volume).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO].delta.
ppm:
1.43 (3H, singlet);
2.06 (3H, singlet);
2.20 (3H, singlet);
2.46 (3H, singlet);
2.8-3.55 (2H, nd);
3.10 (2H, AB type, J=13.5 Hz);
3.32 (3H, singlet);
3.55-3.7 (2H, multiplet);
4.08 (2H, AB type, J=6 Hz);
4.25-4.4 (2H, multiplet);
4.34 (2H, singlet);
4.76 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.93 (2H, doublet, J=9 Hz);
7.24 (2H, doublet, J=9 Hz);
10.0-10.6 (1H, broad, disappeared on adding heavy water).
EXAMPLE 55
t-Butyl
.alpha.-{5-[4-(6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,7,8-tetramethy
lchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate
A mixture of 0.5 g of t-butyl
.alpha.-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-
2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate (prepared as
described in Example 51), 0.2 g of hydroxylamine hydrochloride, 0.2
g of pyridine and 5 ml of methanol was allowed to stand at
25.degree.-30.degree. C. for 5 days. Ethyl acetate and an aqueous
solution of potassium carbonate were added to the mixture, and the
organic layer was separated. The organic layer was dried over
anhydrous sodium sulfate. The solvent was distilled off and the
residue was subjected to silica gel column chromatography (eluted
with a 20:1 by volume mixture of benzene and ethyl acetate) to
obtain the title compound.
Rf value on silica gel thin layer chromatography=0.43 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.45 (3H, singlet);
1.47 (9H, singlet);
1.54 (9H, singlet);
2.07 (3H, singlet);
2.23 (3H, singlet);
2.47 (3H, singlet);
2.85-3.15 (1H, nd);
3.08 (2H, singlet);
3.57 (1H, doublet of doublets, J=4 .delta. 13.5 Hz);
3.97 (2H, singlet);
4.20 (4H, singlet);
4.46 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.87 (2H, doublet, J=9 Hz);
7.15 (2H, doublet, J=9 Hz);
7.5-8.05 (1H, broad).
EXAMPLE 56
Di-t-butyl
.alpha.,.alpha.'-{5-[4-(6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,7,8-t
etramethylchroman
-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate
A mixture of 350 mg of di-t-butyl
.alpha.,.alpha.'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl
-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate
(prepared as described in Example 50), 122 mg of hydroxylamine
hydrochloride, 122 mg of pyridine and 4 ml of methanol was allowed
to stand at 25.degree.-+.degree. C. for 5 days. Ethyl acetate and
an aqueous solution of potassium carbonate were added to the
mixture, and the organic layer was separated. The organic layer was
dried over anhydrous sodium sulfate. The solvent was distilled off
and the residue was subjected to silica gel column chromatography
(eluted with a 20:1 by volume mixture of benzene and ethyl acetate)
to obtain the title compound.
Rf value on silica gel thin layer chromatography=0.48 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.45 (21H, singlet);
1.53 (9H, singlet);
2.08 (3H, singlet);
2.23 (3H, singlet);
2.47 (3H, singlet);
2.9-3.2 (1H, nd);
3.07 (2H, broad singlet);
3.22 (2H, singlet);
3.95 (2H, broad singlet);
4.11 (2H, singlet);
4.18 (2H, singlet);
6.83 (2H, doublet, J=9 Hz);
7.13 (2H, doublet, J=9 Hz);
7.68 (1H, broad singlet).
EXAMPLE 57
Ethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-4-hydroxyimi
no-2,5,7,8-tetramethylchroman-6-yloxy}acetate
Following the procedure described in Example 54, the title compound
was obtained as a pale yellow powder by using 330 mg of ethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8tetra
methyl -4-oxochroman-6-yloxy}acetate (prepared as described in
Example 43), 170 mg of hydroxylamine hydrochloride, 170 mg of
pyridine and 3 ml of methanol.
Rf value on silica gel thin layer chromatography =0.67 (developing
solvent, benzene:ethyl acetate=1:1 by volume).
Mass spectrum (m/e): 556 (M.sup.+).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO].delta.
ppm:
1.27 (3H, triplet, J=7 Hz);
1.43 (3H, singlet);
2.06 (3H, singlet);
2.20 (3H, singlet);
2.46 (3H, singlet);
2.95-3.25 (1H, nd);
3.08 (2H, singlet);
3.43 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.08 (2H, singlet);
4.1-4.4 (2H, nd);
4.30 (2H, singlet);
4.74 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.93 (2H, doublet, J=9 Hz);
7.23 (2H, doublet, J=9 Hz);
10.30 (1H, broad singlet, disappeared on adding heavy water).
EXAMPLE 58
.alpha.-{2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-2,5,7,8-tetra
methylchroman-6yloxy}acetic acid
A mixture of 220 mg of 2-methoxyethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl)9
2,5,7,8-tetramethylchroman-6-yloxy}acetate (prepared as described
in Example 41), 3 ml of a 4N dioxane solution of hydrogen chloride
and 0.3 ml of water was heated under reflux for 5 hours. At the end
of this time, the solvent was distilled off and the residue was
washed with water to give the title compound as a pale yellow
powder.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO].delta.
ppm:
1.38 (3H, singlet);
1.8-2.2 (2H, nd);
2.02 (3H, singlet);
2.15 (6H, singlet);
2.65 (2H, broad triplet, J=7 Hz);
3.08 (1H, doublet of doublets, J=9 .delta. 14 Hz);
3.41 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.00 (2H, singlet);
4.27 (2H, singlet);
4.73 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.92 (2H, doublet, J=9 Hz);
7.23 (2H, doublet, J=9 Hz);
9.9-11.3 (1H, broad, disappeared on adding heavy water).
Mass spectrum (m/e): 499 (M.sup.+).
EXAMPLE .gradient.
.alpha.-{2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)-phenoxymethyl]-2,5,7,8-tetr
amethyl-4-oxochroman -6-yloxy}acetic acid
After eluting the 2-methoxyethyl ester which was obtained from the
silica gel column chromatography described in Example 35, the title
compound was obtained as pale yellow powder by continuing the
elution with a 2:2:1 by volume mixture of ethyl acetate,
tetrahydrofuran and methanol.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 SO].delta.
ppm:
1.41 (3H, singlet);
2.02 (3H, singlet);
2.18 (3H, singlet);
2.46 (3H, singlet);
2.68 (1H, doublet, J=16 Hz);
2.85-3.20 (2H, nd);
3.22 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.01 (2H, singlet);
4.12 (2H, singlet);
4.61 (1H, doublet of doublets, J=4 .delta. 9 Hz);
6.87 (2H, doublet, J=9 Hz);
7.15 (2H, doublet, J=9 Hz).
Mass spectrum (m/e): 513 (M.sup.+).
EXAMPLE 60
.alpha.-{2-[4-(2,4-Dioxothiazolidin-5-ylmethyl)phenoxymethyl]-4-hydroxyimin
o-2,5,7,8-tetramethylchroman-6-yloxy}acetic acid
A mixture of 8.9 mg of ethyl
.alpha.-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxymethyl]-4-hydroxyimi
no-2,5,7,8-tetramethylchroman-6-yloxy}acetate [prepared as
described in Example 57], 1 ml of ethanol and 0.2 ml of a 0.312M
aqueous solution of sodium hydroxide was allowed to stand for 19
hours at 0.degree.-5.degree. C.
After the absence of the starting material had been confirmed by
high pressure liquid chromatography, 0.56 ml of 0.35% w/v aqueous
hydrochloric acid was then added to the reaction mixture. The
solvent was distilled off under reduced pressure, and chloroform
and water were added to the residue.
The pale yellow precipitate was filtered and then washed with
water, to give the title compound.
Fast Atom Bombardment Mass Spectrum (m/e measured with glycerol as
a matrix)
[M+H].sup.+ =529.
[M-H].sup.- =527.
From the above data, the molecular weight was deduced to be
528.
EXAMPLE 61
.alpha.-{5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl]-2,
4-dioxothiazolidin -3yl}acetic acid
A mixture of 1.0 g of t-butyl
.alpha.-{5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl
]-2,4-dioxothiazolidin-3-yl}acetate (prepared as described in
Example 46) and 10 ml of a 4N dioxane solution of hydrogen chloride
was allowed to stand at room temperature overnight. At the end of
this time, the solvent was distilled off and the residue was washed
with water to give the title compound as a pale yellow powder,
softening at 85.degree.-90.degree. C.
Nuclear magnetic Resonance Spectrum: the signal assigned to the
t-butyl group had disappeared, as compared with the spectrum of the
starting material.
Mass spectrum (m/e): 499 (M.sup.+).
EXAMPLE 62
.alpha.-{5-[4-(6-Hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzy
l]-2,4-dioxothiazolidin-3-yl}acetic acid
A mixture of 350 mg of t-butyl
.alpha.-{5-[4-(6-hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benz
yl]-2,4-dioxothiazolidin-3yl}acetate (prepared as described in
Example 49) and 4 ml of a 4N dioxane solution of hydrogen chloride
was treated in the same manner described in Example 61, to give the
title compound as a pale yellow powder, softening at
60.degree.-70.degree. C.
Nuclear Magnetic Resonance Spectrum: the signal assigned to the
t-butyl group had disappeared, as compared with the spectrum of the
starting material.
Mass spectrum (m/e): 513 (M.sup.+).
EXAMPLE 63
.alpha.-{5-[4-(6-Hydroxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2-ylmeth
oxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetic acid
A mixture of 400 mg of t-butyl
.alpha.-{5-[4-)6-hydroxy-4-hydroxyimino-2,5,7,8-tetramethylchroman
-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate (prepared as
described in Example 53) and 5 ml of a 4N dioxane solution of
hydrogen chloride was treated in the same manner described in
Example 61, to give the title compound as a pale brown powder,
softening at 90.degree.-95.degree. C.
Nuclear Magnetic Resonance Spectrum: the signal assigned to the
t-butyl group had disappeared, as compared with the spectrum of the
starting material.
EXAMPLE 64
.alpha.-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benz
yl]-2,4-dioxothiazolidin -3-yl}acetic acid
A mixture of 0.63 g of t-butyl
.alpha.-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-2-ylme
thoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate (prepared as
described in Example 48) and 6 ml of a 4N dioxane solution of
hydrogen chloride was allowed to stand at room temperature
overnight. At the end of this time, the reaction mixture was
treated as the same manner described in Example 61, to give the
title compound as a pale yellow powder, softening at
95.degree.-100.degree. C.
Nuclear Magnetic Resonance Spectrum: the signal assigned to the
t-butyl group had disappeared, as compared with the spectrum of the
starting material.
Mass spectrum (m/e): 557 (M.sup.+).
EXAMPLE 65
.alpha.-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethox
y)benzyl]-2,4-dioxothiazolidin-3-yl}acetic acid
A mixture of 570 mg of t-butyl
.alpha.-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-
2-ylmethoxy)benzyl]-2,4-dioxothiazolidin3-yl}acetate (prepared as
described in Example 51) and 6 ml of a 4N dioxane solution of
hydrogen chloride was treated in the same manner described in
Example 61, to give the title compound as a pale yellow powder,
softening at 80.degree.-85.degree. C.
Nuclear Magnetic Resonance Spectrum: the signal assigned to the
t-butyl group had disappeared, as compared with the spectrum of the
starting material.
Mass spectrum (m/e): 571 (M.sup.+).
EXAMPLE 66
.alpha.-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethylchroman-2
-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetic acid
A mixture of 370 mg of t-butyl
.alpha.-{5-[4-(6-t-butoxycarbonylmethoxy-4-hydroxyimino-2,5,7,8-tetramethy
lchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidin-3-yl}acetate
(prepared as described in Example 55) and 4 ml of a 4N dioxane
solution of hydrogen chloride was treated in the same manner
described in Example 61, to give the title compound as a pale
yellow powder, softening at 90.degree.-100.degree. C.
Nuclear Magnetic Resonance Spectrum: the signal assigned to the
t-butyl group had disappeared, as compared with the spectrum of the
starting material.
EXAMPLE 67
.alpha.,.alpha.'-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethylchroman-2-ylmet
hoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetic acid
A mixture of 0.41 g of di-t-butyl
.alpha.,.alpha.'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchrom
an-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate
(prepared as described in Example 47) and 4 ml of a 4N dioxane
solution of hydrogen chloride was allowed to stand at room
temperature overnight. At the end of this time, the reaction
mixture was treated in the same manner described in Example 61, to
give the title compound as a pale yellow powder, softening at
105.degree.-110.degree. C.
Nuclear Magnetic Resonance Spectrum: the signal assigned to the
t-butyl group had disappeared, as compared with the spectrum of the
starting material.
Mass spectrum (m/e): 615 (M.sup.+).
EXAMPLE 68
.alpha.,.alpha.'-{5-[4-(6-Carboxymethoxy-2,5,7,8-tetramethyl-4-oxochroman-2
-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetic acid
A mixture of 340 mg of di-t-butyl
.alpha.,.alpha.'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl
-4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate
(prepared as described in Example 50) and 4 ml of a 4N dioxane
solution of hydrogen chloride was treated in the same manner
described in Example 61, to give the title compound as a pale
yellow powder, softening at 105.degree.-110.degree. C.
Nuclear Magnetic Resonance Spectrum: the signal assigned to the
t-butyl group had disappeared, as compared with the spectrum of the
starting material.
Mass Spectrum (m/e): 629 (M.sup.+).
EXAMPLE 69
.alpha.,.alpha.'-{5-[4-(6-Carboxymethoxy-4-hydroxyimino-2,5,7,8-tetramethyl
chroman-2-ylmethoxy)benzyl
]-2,4-dioxothiazolidine-3,5-diyl}diacetic acid
A mixture of 270 mg of di-t-butyl
.alpha.,.alpha.'-{5-[4-(6-t-butoxycarbonylmethoxy-4-hydroxyimino
-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-
diyl}diacetate (prepared as described in Example 56) and 3 ml of a
4N dioxane solution of hydrogen chloride was treated in the same
manner described in Example 61, to give the title compound as a
pale yellow powder, softening at 90.degree.-100.degree. C.
Nuclear Magnetic Resonance Spectrum: the signal assigned to the
t-butyl group had disappeared, as compared with the spectrum of the
starting material.
EXAMPLE 70
5-[4-(6-Hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine-
2,4-dione sulfuric acid ester
A solution of 5 g of
5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)benzyl]thiazolidine
-2,4-dione (synthesized as described in copending U.S. Ser. No.
644,996) in 10 ml of pyridine was added to a solution of 7.3 g
(62.64 mmole) of chlorosulfonic acid in 20 ml of pyridine, and the
reaction mixture was heated at 70.degree.-80.degree. C. for 1 hour.
At the end of this time, petroleum ether was added to the reaction
mixture, the supernatant liquid was removed by decantation, and
then these procedures were repeated a further 2 times. 10 ml of
water were added to the resulting residue. The reaction mixture was
adjusted to a pH value of 6.5 with a 2N aqueous solution of sodium
hydroxide and extracted with ethyl acetate. The ethyl acetate was
distilled from the extract under reduced pressure, to give 5.72 g
of the title compound as a white powder, melting at
140.5.degree.142.5.degree. C.
Infrared Absorption Spectrum (Nujol-trade mark-mull): .nu..sub.max
cm.sup.-1 :
3600, 3330, 1270, 1050.
Nuclear Magnetic Resonance Spectrum:(CD.sub.3 CN) .delta. ppm:
7.2 (2H, doublet);
6.9 (2H, doublet);
4.6 (1H, doublet of doublets);
4.0 (1H, doublet);
3.9 (1H, doublet);
3.3 (1H, doublet of doublets);
3.1 (1H, doublet of doublets);
2.6 (2H, triplet);
2.19 (3H, singlet);
2.18 (3H, singlet);
2.1 (1H, multiplet);
2.0 (3H, singlet);
1.9 (1H, multiplet);
1.4 (3H, singlet).
Fast Atom Bombardment Mass Spectrum (m/e measured with glycerol as
a matrix)
(M+H).sup.+ =522;
(M-H).sup.- =520.
From this, we concluded that molecular weight is 521.
PREPARATION 1
Ethyl 6-hydroxy-5,7,8-trimethyl-4-oxochroman-2-carboxylate (Step
E1)
12 g of ethyl
6-hydroxy-5,7,8-trimethyl-4-oxo-2H-chromene-2-carboxylate [prepared
as described in J. Med Chem., 18, 934 (1975)] were dissolved in 250
ml of dimethylformamide and reduced catalytically in the presence
of 16 g of 10% w/w palladium-on-carbon, under a hydrogen pressure
of 5 atmospheres at 50.degree. to 60.degree. C. for 7 hours. The
catalyst was then filtered off, and the filtrate was mixed with a
large amount of water. The crystals which separated were collected
by filtration and then recrystallized from ethyl acetate, to give
the title compound, melting at 120.degree.-121.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.26 (3H, triplet, J=7 Hz);
2.23 (6H, singlet);
2.52 (3H, singlet);
2.98 (2H, doublet, J=7 Hz);
4.24 (2H, quartet, J=7 Hz);
4.83 (1H, singlet);
4.94 (1H, triplet, J=7 Hz).
The filtrate from which the title compound had been filtered off
was extracted with ethyl acetate. The solution was dried over
anhydrous sodium sulfate, and the solvent was distilled off. The
residue was purified by silica gel column chromatography, eluted
with a 1:1 by volume mixture of hexane and ethyl acetate. The first
fraction gave the title compound, while the second fraction gave
ethyl 4,6-dihydroxy-5,7,8-trimethylchroman-2-carboxylate, melting
at 138.degree.-144 .degree. C.
PREPARATION 2
Ethyl
6-hydroxy-5,7,8trimethylchromanspiro-4,2'-(1',3'-dithiane)-2-carboxylate
(Step E2)
20 ml of a boron trifluoride-acetic acid complex salt (boron
trifluoride content 40% w/w) were added dropwise to 500 ml of a
chloroform solution containing 16.6 g of ethyl
6-hydroxy-5,7,8-trimethyl-4-oxochroman-2-carboxylate (prepared as
described in Preparation 1) and 9.7 g of 1,3-propanedithiol in an
ice bath, and the reaction mixture was allowed to stand for 24
hours at room temperature. The reaction mixture was then poured
into ice-water, neutralized with potassium carbonate and extracted
with ethyl acetate. The ethyl acetate extract was dried over
anhydrous sodium sulfate and the solvent was distilled off.
Recrystallization of the residue from ethyl acetate afforded the
title compound, melting at 186.degree.-188.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.35 (3H, triplet, J=7 Hz);
1.8-2.4 (2H, nd);
2.18 (6H, singlet);
2.5-2.9 (3H, nd);
2.80 (3H, singlet);
3.0-3.5 (3H, multiplet);
4.31 (2H, quartet, J=7 Hz);
4.50 (1H, singlet);
4.79 (1H, doublet of doublets, J=2 .delta. 10 Hz).
PREPARATION 3
Ethyl 6
methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)-2-carboxy
late (Step E3)
A mixture of 6.6 g of ethyl
6-hydroxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)-2-carboxylate
(prepared as described in Preparation 2), 100 ml of
dimethylformamide and 1 g of a 55% w/w suspension of sodium hydride
in mineral oil was subjected to ultrasonic treatment for mixing at
room temperature for 1 hour, and then, whilst ice-cooling, 3 g of
chloromethyl methyl ether were added, and the mixture was allowed
to stand at room temperature overnight. Water was added to the
reaction mixture, which was then extracted with ethyl acetate. The
water layer was extracted additionally with benzene. Both the ethyl
acetate and benzene extracts were washed with water three times,
after which the extracts were combined and dried over anhydrous
sodium sulfate. The solvent was distilled off and the residue was
purified by silica gel column chromatography, eluted with a 5:1 by
volume mixture of hexane and ethyl acetate, to give the title
compound.
Rf value on silica gel thin layer chromatography=0.21 (developing
solvent, hexane:ethyl acetate=5:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.34 (3H, triplet, J=7 Hz);
1.7-2.4 (2H, nd);
2.16 (3H, singlet);
2.21 (3H, singlet);
2.5-3.0 (3H, nd);
2.87 (3H, singlet);
3.0-3.5 (3H, nd);
3.60 (3H, singlet);
4.30 (2H, quartet, J=7 Hz);
4.7-5.0 (1H, nd);
4.89 (2H, singlet).
PREPARATION 4
2-Hydroxymethyl-2-isobutyl-6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2
'-(1',3'-dithiane) (Steps E4 & E5)
15 ml of a hexane solution of butyllithium (butyllithium content
1.62 mmole/ml) were added dropwise at a temperature of -60.degree.
C. to -50.degree. C. to 90 ml of a tetrahydrofuran solution
containing 3 g of diisopropylamine, and the mixture was allowed to
stand for 20 minutes at room temperature. 4.8 g of ethyl
6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)-2-carbo
xylate (prepared as described in Preparation 3) were added at
-60.degree. C. to the mixture, which was then stirred for 10
minutes at the same temperature. 4.1 g of isobutyl bromide were
added, and the mixture was stirred for 30 minutes at the same
temperature, and then stirred at room temperature for 1.5 hours.
Another 3 g of isobutyl bromide were added, and the mixture was
heated at 40.degree. C. for 5 hours. The reaction mixture was then
cooled to -50.degree. C., 0.6 g of lithium aluminum hydride were
added, and the mixture was stirred for 1 hour at room temperature.
Benzene, ethyl acetate and water were added to this reaction
mixture. The organic layer was separated, washed with water and
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure. The residue was purified by silica gel
column chromatography, eluted with a 5:1 by volume mixture of
hexane and ethyl acetate, to give the title compound.
Rf value on silica gel thin layer chromatography=0.16 (developing
solvent, hexane:ethyl acetate=5:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.03 (3H, doublet, J=6 Hz);
1.04 (3H, doublet, J=6 Hz);
1.70 (2H, doublet, J=6 Hz);
1.8-2.3 (3H, nd);
2.08 (3H, singlet);
2.20 (3H, singlet);
2.3-3.0 (4H, nd);
2.91 (3H, singlet);
3.05-3.95 (5H, nd);
3.62 (3H, singlet);
4.88 (2H, singlet).
PREPARATION 5
2-Isobutyl-6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman
spiro-4,2'-(1',3'-dithiane) (Step E6)
4 ml of ethanol were added to a mixture of 0.6 g of a 55% w/w
suspension of sodium hydride in mineral oil and 20 ml of
tetrahydrofuran, followed by 20 ml of a tetrahydrofuran solution
containing 3.2 g of
2-hydroxymethyl-2-isobutyl-6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,
2'-(1',3'-dithiane) (prepared as described in Preparation 4). The
solvent was then distilled off under reduced pressure to dryness.
The residue was mixed with 30 ml of dimethylformamide and heated at
40.degree. C. for 1 hour under reduced pressure. 10 g of
p-nitrochlorobenzene were then added to the reaction mixture, and
the mixture was heated at 50.degree. C. for 2 hours, mixed with
water and extracted with benzene. The benzene extract was washed
twice with water and dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure. The residue was
purified by silica gel column chromatography eluted with a 6:1 by
volume mixture of hexane and ethyl acetate, to give the title
compound.
Rf value on silica gel thin layer chromatography= 0.54 (developing
solvent, hexane:ethyl acetate=2:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.02 (3H, doublet, J=6 Hz);
1.09 (3H, doublet, J=6 Hz);
1.83 (2H, doublet, J=6 Hz);
1.8-2.3 (3H, nd);
2.11 (3H, singlet);
2.22 (3H, singlet);
2.3-2.9 (3H, nd);
2.89 (3H, singlet);
3.0-3.7 (3H, nd);
3.62 (3H, singlet);
3.92 (1H, doublet, J=4.5 Hz);
4.50 (1H, doublet, J=4.5 Hz);
4.90 (2H, singlet);
6.90 (2H, doublet, J=4.5 Hz);
8.17 (2H, doublet, J=4.5 Hz).
PREPARATION 6
(a)
2-Isobutyl-6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroma
n-4-one and (b)
6-hydroxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one
(Step E7)
A mixture of 3.3 g of
2-isobutyl-6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroma
nspiro -4,2'-(1',3'-dithiane) (prepared as described in Preparation
5), 4 g of mercuric chloride, 1.4 g of mercuric oxide and 30 ml of
10% v/v aqueous methanol was heated under reflux for 2 hours. The
reaction mixture was then mixed with diethyl ether, and the
insoluble residue was filtered off. The filtrate was washed with an
aqueous solution of sodium chloride and then with an aqueous
solution of ammonium sulfate, and dried over anhydrous sodium
sulfate. The solvent was distilled off and the residue was purified
by silica gel column chromatography eluted with a 4:1 by volume
mixture of hexane and ethyl acetate, to give the title compounds
(a) and (b) separately.
Silica gel thin layer chromatography (developing solvent,
hexane:ethyl acetate=2:1 by volume),
(a) Rf value=0.48
(b) Rf value=0.40.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
(a) 1.01 (6H, doublet, J=6 Hz);
1.84 (2H, singlet);
1.6-2.1 (1H, singlet);
2.12 (3H, singlet);
2.27 (3H, singlet);
2.58 (3H, singlet);
2.81 (1H, doublet, J=19 Hz);
3.00 (1H, doublet, J=19 Hz);
3.62 (3H, singlet);
4.14 (1H, doublet, J=11 Hz);
4.25 (1H, doublet, J=11 Hz);
4.89 (2H, singlet);
6.95 (2H, doublet, J=4.5 Hz);
8.20 (2H, doublet, J=4.5 Hz).
(b) 0.98 (3H, doublet, J=6 Hz);
1.00 (3H, doublet, J=6 Hz);
1.80 (2H, doublet, J=6 Hz);
1.65-2.1 (1H, nd);
2.13 (3H, singlet);
2.23 (3H, singlet);
2.57 (3H, singlet);
2.82 (1H, doublet, J=14 Hz);
3.00 (1H, doublet, J=14 Hz);
4.13 (1H, doublet, J=12 Hz);
4.27 (1H, doublet, J=12 Hz);
4.66 (1H, singlet);
6.95 (2H, doublet, J=9 Hz);
8.19 (2H, doublet, J=9 Hz).
PREPARATION 7
6-Acetoxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one
A mixture of 1.5 g of
6-hydroxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one
(prepared as described in Preparation 6) and 30 ml of pyridine was
mixed with 3 g of acetic anhydride and stirred for 35 hours at room
temperature. The reaction mixture was then condensed by evaporation
under reduced pressure, mixed with water and extracted with ethyl
acetate and benzene. The extract was dried over anhydrous sodium
sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography, using
a 5:1 by volume mixture of hexane and ethyl acetate, to give the
title compound.
Rf value on silica gel thin layer chromatography=0.42 (developing
solvent, hexane:ethyl acetate=2:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.01 (6H, doublet, J=6 Hz);
1.7-2.2 (3H, nd);
2.09 (3H, singlet);
2.12 (3H, singlet);
2.33 (3H, singlet);
2.42 (3H, singlet);
2.91 (2H, AB type, J=18 Hz);
4.13 .delta. 4.25 (2H, AB type, J=9 Hz);
6.95 (2H, doublet, J=9 Hz);
8.20 (2H, doublet, J=9 Hz).
PREPARATION 8
6-Acetoxy-2-(4-aminophenoxymethyl)-2-isobutyl-5,7,8-trimethylchroman-4-one
1.4 g of
6-acetoxy-2-isobutyl-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one
(prepared as described in Preparation 7) was dissolved in 35 ml of
methanol, and, in the presence of 1 g of 10% w/w
palladium-on-carbon, it was reduced for 3 hours under about 1
atmosphere (about 1 bar) pressure of hydrogen. The catalyst was
filtered off, and the solvent was then distilled off under reduced
pressure to give the title compound.
Rf value on silica gel thin layer chromatography=0.54 (developing
solvent, ethyl acetate).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.97 (6H, doublet, J=6 Hz);
1.6-2.2 (3H, nd);
2.08 (3H, singlet);
2.14 (3H, singlet);
2.32 (3H, singlet);
2.42 (3H, singlet);
2.74 .delta. 3.02 (2H, AB type, J=16 Hz);
3.2 -3.7 (2H, broad singlet);
3.94 .delta. 4.06 (2H, AB type, J=9 Hz);
6.58 (2H, doublet, J=9 Hz);
6.73 (2H, doublet, J=9 Hz).
PREPARATION 9
Ethyl
3-[4-(6-acetoxy-2-isobutyl-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)phenyl
]-2-chloropropionate (Step D3)
1.5 ml of concentrated hydrochloric acid was added to mixture of
1.1 g of
6-acetoxy-2-(4-aminophenoxymethyl)-2-isobutyl-5,7,8-trimethylchroman-4-one
(prepared as described in Preparation 8) and 20 ml of acetone under
a nitrogen stream and at room temperature. This was followed by 0.8
g of sodium nitrite and 0.3 ml of water, and then by 4 g of ethyl
acrylate. 0.1 g of cuprous oxide was added at room temperature to
the reaction mixture, which was then stirred for 1 hour. Water was
then added, and the mixture was extracted with benzene. The benzene
extract was washed with water and dried over anhdyrous sodium
sulfate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography using
a 5.1 by volume mixture of hexane and ethyl acetate as eluent, to
give the title compound.
Rf value on silica gel thin layer chromatography=0.74 (developing
solvent, hexane:ethyl acetate=1:2 by volume).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.98 (6H, doublet, J=6 Hz);
1.25 (3H, triplet, J=7 Hz);
1.5-2.2 (3H, nd);
2.08 (3H, singlet);
2.13 (3H, singlet);
2.32 (3H, singlet);
2.42 (3H, singlet);
2.78 .delta. 3.01 (2H, AB type, J=17 Hz);
2.8-3.5 (2H, nd);
3.8-4.5 (5H, nd);
6.82 (2H, doublet, J=9 Hz);
7.11 (2H, doublet, J=9 Hz).
PREPARATION 10
Ethyl 6-hydroxy-5,7,8-trimethylchroman-2-carboxylate (Step C4)
14 g of ethyl
6-hydroxy-5,7,8-trimethyl-4-oxo-2H-chromene-2-carboxylate [prepared
as described in J. Med. Chem., 18, 934 (1975)] were dissolved in
320 ml of acetic acid, and the resulting solution was catalytically
reduced for 1 hour at 60.degree.-65.degree. C., under a hydrogen
pressure of 3 atmospheres and in the presence of 3.5 g of 10% w/w
palladium-on-carbon. The catalyst was filtered off, and the
filtrate was poured into water. The white crystals which separated
were collected by filtration, to give the title compound, melting
at 108.degree.-109.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.28 (3H, triplet, J=7 Hz);
2.07 (3H, singlet);
2.17 (6H, singlet);
1.9-2.3 (2H, nd);
2.65 (2H, broad triplet, J=7 Hz);
4.22 (2h, broad triplet, J=7 hz);
4.1-4.3 (1H, nd);
4.60 (1H, doublet of doublets, J=7 .delta. 4 Hz).
PREPARATION 11
Ethyl 6-methoxymethoxy-5,7,8-trimethylchroman-2-carboxylate (Step
C5)
3 g of a 55% w/w suspension of sodium hydride in mineral oil were
washed twice with cyclohexane. A mixture of 14.3 g of ethyl
6-hydroxy-5,7,8-trimethylchroman-2-carboxylate (prepared as
described in Preparation 10) and 130 ml of dimethylformamide was
added slowly to this suspension under a nitrogen stream at
5.degree.-10.degree. C. The reaction mixture was stirred for 1
hour, and then cooled in ice to 3.degree.-5.degree. C., after which
5.6 g of chloromethyl methyl ether were added dropwise. After this
addition, the reaction mixture was stirred for 1 hour at room
temperature, poured into ice-water, and then extracted with
cyclohexane. The cyclohexane extract was washed with water and
dried over anhydrous sodium sulfate. The solvent was then distilled
off under reduced pressure. The residue was purified by silica gel
column chromatography using a 25:1 by volume mixture of benzene and
ethyl acetate as eluent, to give the title compound.
Rf value on silica gel thin layer chromatography=0.41 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
1.27 (3H, triplet, J=7 Hz);
2.0-2.4 (2H, nd);
2.15 (3H, singlet);
2.16 (3H, singlet);
2.2 (3H, singlet);
2.64 (2H, broad triplet, J=7 Hz);
3.61 (3H, singlet);
4.24 (2H, quartet, J=7 Hz);
b 4.64 (1H, doublet of doublets, J=4 .delta. 7 Hz);
4.87 (2H, singlet).
PREPARATION 12
Ethyl 6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-carboxylate
(Step C6)
7.8 ml of a hexane solution containing 1.62 mmole/ml of
butyllithium were added dropwise to a mixture of 2 g of
diisopropylamine and 80 ml of tetrahydrofuran under a nitrogen
stream at a temperature from -60.degree. to -50.degree. C. The
resulting mixture was then allowed to stand for 10 minutes at room
temperature, after which about 10 ml of tetrahydrofuran containing
4 g of ethyl 6-methoxymethoxy-5,7,8-trimethylchroman-2-carboxylate
(prepared as described in Preparation 11) were added and the
mixture was stirred for 1 hour at -60.degree. C. About 20 ml of
tetrahydrofuran containing 5 g of octyl bromide were added, and the
mixture was stirred for 1 hour at -60.degree. C. and then for 1
hour at room temperature, after which it was heated for 1 hour at
50.degree. C. The reaction mixture was then poured into ice-water
and extracted with ethyl acetate. The extract was washed with water
and dried over anhydrous sodium sulfate. The solvent was removed by
distillation under reduced pressure, and the residue was subjected
to silica gel column chromatography eluted with benzene, to give
the title compound.
Rf value on silica gel thin layer chromatography=0.58 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.89 (3H, broad triplet, J=6 Hz);
1.15 (3H, triplet, J=7 Hz);
1.2-1.6 (12H, multiplet);
1.6-2.4 (4H, multiplet);
2.1 (3H, singlet);
2.18 (3H, singlet);
2.2 (3H, singlet);
2.4-2.7 (2H, multiplet);
3.59 (3H, singlet);
4.11 (2H, quartet, J=7 Hz);
4.85 (2H, singlet).
PREPARATION 13
6-Methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-yl-methanol (Step
A1')
10 ml of tetrahydrofuran containing 3.3 g of ethyl
6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-carboxylate
(prepared as described in Preparation 12) were added dropwise to a
mixture of 0.45 g of lithium aluminum hydride and 30 ml of
tetrahydrofuran under a nitrogen stream, and whilst ice-cooling.
The resulting mixture was stirred for 3 hours at room temperature.
Ethyl acetate and 5% w/v aqueous hydrochloric acid were then added
to the reaction mixture, whilst ice-cooling, and the organic layer
was separated. Then the aqueous layer was extracted with ethyl
acetate. The organic layer and the extract were combined, washed
with a saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under reduced pressure, to give the title compound.
Rf value on silica gel thin layer chromatography=0.45 (developing
solvent, benzene:ethyl acetate=10.1 by volume).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.7-1.0 (3H, multiplet);
1.0-2.3 (16H, multiplet);
2.10 (3H, singlet);
2.15 (3H, singlet);
2.20 (3H, singlet);
2.59 (2H, broad triplet, J=7 Hz);
3.6 (5H, singlet);
4.87 (2H, singlet).
PREPARATION 14
6-Methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman
(Step A2)
0.38 g of a 55% w/w suspension of sodium hydride in mineral oil was
added to a mixture of 3 g of
6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethanol
(prepared as described in Preparation 13) and 25 ml of
dimethylformamide under a nitrogen stream at room temperature, and
the resulting mixture was heated for 2 hours at 50.degree. C. A
mixture of 1.4 g of p-chloronitrobenzene and 2 ml of benzene was
then added dropwise, whilst ice-cooling, and the resulting mixture
was heated for 2 hours at 50.degree. C. The reaction mixture was
then poured into ice-water and extracted with benzene. The extract
was washed with water and dried over anhydrous sodium sulfate. The
solvent was removed by distillation under reduced pressure, and the
residue was purified by silica gel column chromatography eluted
with benzene, to give the title compound.
Rf value on silica gel thin layer chromatography=0.46 (developing
solvent, benzene).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.7-1.0 (3H, multiplet);
1.0-1.9 (14H, multiplet);
1.9-2.3 (2H, nd);
2.06 (3H, singlet);
2.15 (3H, singlet);
2.19 (3H, singlet);
2.6 (2H, broad triplet, J=7 Hz);
3.60 (3H, singlet);
4.05 (2H, singlet);
4.87 (2H, singlet);
6.97 (2H, doublet, J=9 Hz);
8.18 (2H, doublet, J=9 Hz).
PREPARATION 15
6-Hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman
(Step A3, Deprotection)
A mixture of 3.7 g of
6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman
(prepared as described in Preparation 14), 10 ml of acetic acid, 30
ml of benzene and 0.75 ml of 10% w/v aqueous sulfuric acid was
heated under reflux for 30 minutes. The reaction mixture was then
poured into water and extracted with benzene. The extract was
washed with water and dried over anhydrous sodium sulfate. The
solvent was removed by distillation under reduced pressure, to give
the title compound.
Rf value on silica gel thin layer chromatography=0.34 (developing
solvent, benzene).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.7-1.0 (3H, multiplet);
1.0-1.85 (14H, multiplet);
1.85-2.2 (2H, nd);
2.10 (6H, singlet);
2.16 (3H, singlet);
2.63 (2H, broad triplet, J=7 Hz);
4.06 (2H, singlet);
4.19 (1H, singlet, disappeared on adding heavy water);
6.97 (2H, doublet, J=9 Hz);
8.19 (2H, doublet, J=9 Hz).
PREPARATION 16
6-Acetoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman
(Step A3, Acylation)
1.2 g of acetic anhydride was added to a mixture of 3.5 g of
6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman
(prepared as described in Preparation 15), 10 ml of pyridine and 10
ml of benzene, and the mixture was stirred for 2hours at room
temperature. The reaction mixture was then poured into water and
extracted with benzene. The extract was washed with 5% w/v aqueous
hydrochloric acid and water, successively in that order, and dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under reduced pressure, to give the title
compound.
Rf value on silica gel thin layer chromatography=0.4 (developing
solvent, benzene).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.75-1.0 (3H, multiplet);
1.1-1.65 (12H, multiplet);
1.65-2.15 (4H, nd);
1.99 (3H, singlet);
2.04 (3H, singlet);
2.08 (3H, singlet);
2.32 (3H, singlet);
2.63 (2H, broad triplet, J=7 Hz);
4.07 (2H, singlet);
6.98 (2H, doublet, J=9 Hz);
8.20 (2H, doublet, J=9 Hz).
PREPARATION 17
6-Acetoxy-2-(4-aminophenoxymethyl)-5,7,8-trimethyl-2-octylchroman
(Step A3, Hydrogenation)
Using Paar's hydrogenation apparatus, a mixture of 4 g of
6-acetoxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)-2-octylchroman
(prepared as described in Preparation 16), 0.8 g of 10% w/w
palladium-on-carbon, 30 ml of methanol and 10 ml of benzene was
stirred for 5 hours under 3-5 atmospheres (about 3-5 bars) pressure
or hydrogen. The catalyst was filtered off, and the filtrate was
condensed by evaporation under reduced pressure. The crystals thus
obtained were washed with hexane to give the title compound,
melting at 112.degree.-114.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.7-1.05 (3H, multiplet);
1.05-1.65 (12H, multiplet);
1.65-2.2 (4H, nd);
1.97 (3H, singlet);
2.02 (3H, singlet);
2.10 (3H, singlet);
2.31 (3H, singlet);
2.59 (2H, broad triplet, J=7 Hz);
3.0-3.7 (2H, broad singlet, disappeared on adding heavy water);
3.86 (2H, singlet);
6.62 (2H, doublet, J=10 Hz);
6.75 (2H, doublet, J=10 Hz).
PREPARATION 18
Ethyl
30[4-(6-acetoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethoxy)phenyl]-2-chlor
opropionate (Step A4)
3.5 ml of concentrated hydrochloric acid, 1.7 ml of water
containing 0.61 g of sodium nitrite and 7.2 ml of ethyl acrylate
were added dropwise successively, in that order, under a nitrogen
stream and at 5.degree.-10.degree. C., to a mixture of 3.2 g of
6-acetoxy-2-(4-aminophenoxy-methyl)-5,7,8-trimethyl-2-octylchroman
(prepared as described in Preparation 17) and 35 ml of acetone. The
reaction mixture was then heated to 40.degree.-43.degree. C. (inner
temperature), and 0.1 g of cuprous oxide was slowly added. After
about 30 minutes, nitrogen generation ceased. The reaction mixture
was then poured into water and extracted with benzene. The extract
was washed with water and dried over anhydrous sodium sulfate. The
solvent was removed by distillation under reduced pressure. The
residue was purified by silica gel column chromatography using a
10:1 by volume mixture of cyclohexane and ethyl acetate as eluent,
to give the title compound.
Rf value on silica gel thin layer chromatography=0.27 (developing
solvent, cyclohexane:ethyl acetate=9:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.8-1.05 (3H, multiplet);
1.05-1.65 (15H, multiplet);
1.65-2.2 (4H, nd);
1.97 (3H, singlet);
2.03 (3H, singlet);
2.09 (3H, singlet);
2.30 (3H, singlet);
2.6 (2H, broad triplet, J=7 Hz);
3.07 (1H, doublet of doublets, J=7 .delta. 14 Hz);
3.30 (1H, doublet of doublets, J=7 .delta. 14 Hz);
3.92 (2H, singlet);
4.18 (2H, quartet, J=7 Hz);
4.36 (1H, triplet, J=7 Hz);
6.85 (2H, doublet, J=9 Hz);
7.13 (2H, doublet, J=9 Hz).
PREPARATION 19
6-Acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)chr
oman-4-one (Step D1)
A mixture of 23 g of
5-acetoxy-2-hydroxy-4-(1,1,3,3-tetramethylbutyl)acetophenone, 14.7
g of 1-(4-nitrophenoxy)-2-propanone, 8 g of pyrrolidine and 300 ml
of benzene was stirred for 3 hours at room temperature, and then
heated under reflux for 10 hours. The reaction mixture was then
poured into ice-water and extracted with benzene. The extract was
washed with 5% w/v aqueous hydrochloric acid and water successively
in that order, and then dried over anhydrous sodium sulfate. The
solvent was removed by distillation under reduced pressure. The
residue was mixed with 15 g of acetic anhydride and 400 ml of
pyridine, and the mixture was allowed to stand for 1 day at room
temperature. The reaction mixture was then poured into ice-water
and extracted with benzene. The extract was washed with 5% w/v
aqueous hydrochloric acid and water in that order, and then dried
over anhydrous sodium sulfate. The solvent was removed by
distillation under reduced pressure. The residue was purified by
silica gel column chromatography, eluted with a 20:1 by volume
mixture of benzene and ethyl acetate, and recrystallized from
methanol, to give the title compound, melting at
165.5.degree.-167.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.76 (9H, singlet);
1.36 (6H, singlet);
1.57 (3H, singlet);
1.83 (2H, singlet);
2.32 (3H, singlet);
2.74 (1H, doublet, J=17 Hz);
3.10 (1H, doublet, J=17 Hz);
4.11 .delta. 4.24 (2H, AB type, J=9 Hz);
6.95 (2H, doublet J=9 Hz);
6.98 (1H, singlet);
7.50 (1H, singlet);
8.20 (2H, doublet, J=9 Hz).
PREPARATION 20
6-Acetoxy-4-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethy
lbutyl)chroman (Step F1)
1 g of sodium borohydride was added, whilst ice-cooling, to a
mixture of 100 ml of methanol and 10 ml of benzene containing 13 g
of
6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)ch
roman-4-one (prepared as described in Preparation 19), and the
mixture was stirred for 30 minutes whilst ice-cooling. The reaction
mixture was then poured into ice-water, neutralized with 10% w/v
aqueous hydrochloric acid and extracted with benzene. The extract
was washed with water and dried over anhydrous sodium sulfate. The
solvent was removed by distillation under reduced pressure. The
residue was purified by silica gel column chromatography, eluted
with a 4:1 by volume mixture of benzene and ethyl acetate, to give
the title compound.
Rf value on silica gel thin layer chromatography=0.32 (developing
solvent, benzene:ethyl acetate=4:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.77 (9H, singlet);
1.34 (6H, singlet);
1.54 (3H, singlet);
1.80 (2H, singlet);
1.85-2.25 (1H, nd);
2.29 (3H, singlet);
2.48 (1H, doublet of doublets, J=7 .delta. 14 Hz);
4.02 (2H, AB type, J=12 Hz);
4.7-5.0 (1H, multiplet);
6.85 (1H, singlet);
6.95 (2H, doublet, J=9 Hz);
7.08 (1H, singlet);
8.18 (2H, doublet, J=9 Hz).
PREPARATION 21
(a)
6-Hydroxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)-2
H-chromene and (b)
6-Acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)-2
H-chromene (Step F3)
A solution of 10.2 g of
6-acetoxy-4-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetrameth
ylbutyl)chroman (prepared as described in Preparation 20) and 0.4 g
of p-toluenesulfonic acid in 200 ml of benzene was heated under
reflux for 30 minutes under a nitrogen stream. The reaction mixture
was then poured into ice-water and extracted with benzene. The
extract was washed with water and dried over anhydrous sodium
sulfate. The solvent was removed by distillation under reduced
pressure. The residue was purified by silica gel column
chromatography, eluted with benzene, to give the title compounds
(a) and (b).
Rf value on silica gel thin layer chromatography (developing
solvent, benzene:ethyl acetate=20:1 by volume)=0.53 and 0.50,
respectively.
Nuclear Magnetic Resonance Spectrum (a) (CDCl.sub.3) .delta.
ppm:
0.75 (9H, singlet);
1.38 (6H, singlet);
1.56 (3H, singlet);
1.89 (2H, singlet);
4.09 (2H, singlet);
4.43 (1H, singlet, disappeared on adding heavy water);
5.63 (1H, doublet, J=10 Hz);
6.32 (1H, singlet);
6.41 (1H, doublet, J=10 Hz);
6.73 (1H, singlet);
6.96 (2H, doublet, J=9 Hz);
8.20 (2H, doublet, J=9 Hz).
Nuclear Magnetic Resonance Spectrum (b) (CDCl.sub.3) .delta.
ppm:
0.76 (9H, singlet);
1.32 (6H, singlet);
1.58 (3H, singlet);
1.79 (2H, singlet);
2.29 (3H, singlet);
4.10 (2H, singlet);
5.62 (1H, doublet, J=10 Hz);
6.43 (1H, doublet, J=10 Hz);
6.69 (1H, singlet);
6.79 (1H, singlet);
6.93 (2H, doublet, J=9 Hz);
8.18 (2h, doublet, J=9 Hz).
PREPARATION 22
6-Acetoxy-2-(4-aminophenoxymethyl)-2-methyl-7-(1,1,3,3-tetramethylbutyl)chr
oman (Step F5)
Using Paar's hydrogenation apparatus, a mixture of 9.1 g of
6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)-2
H-chromene (prepared as described in Preparation 21), 2g of 10% w/w
palladium-on-carbon and 150 ml of methanol was stirred for 10 hours
under 3-5 atmospheres (about 3-5-bars) pressure of hydrogen. The
catalyst was filtered off, and the filtrate was condensed by
evaporation under reduced pressure. The residue was purified by
silica gel column chromatography, eluted with a 10:1 by volume
mixture of benzene and ethyl acetate, to give the title
compound.
Rf value on silica gel thin layer chromatography=0.27 (developing
solvent, benzene:ethyl acetate=9:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.77 (9H, singlet);
1.34 (6H, singlet);
1.42 (3H, singlet);
1.7-2.2 (2H, nd);
1.78 (2H, singlet);
2.27 (3H, singlet);
2.65 (2H, broad quartet, J=7 Hz);
3.36 (2H, broad singlet, disappeared on adding heavy water);
3.85 (2H, AB type J9 Hz);
6.54-6.88 (6H, multiplet).
PREPARATION 23
Ethyl
3-{4-[6-acetoxy-2-methyl-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmethoxy]p
henyl{-2-chloropropionate (Step A4)
Following the same procedure as described in Preparation 18, 7.9 g
of
6-acetoxy-2-(4-aminophenoxymethyl)-2-methyl-7-(1,1,3,3-tetramethylbutyl)
chroman (prepared as described in Preparation 22), 1.6 g of sodium
nitrite, 9 ml of concentrated hydrochloric acid, 18 g of ethyl
acrylate, 260 mg of cuprous oxide, 90 ml of acetone and about 5 ml
of water were reacted, to give the title compound.
Rf value on silica gel thin layer chromatography=0.55 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.78 (9H, singlet);
1.22 (3H, triplet, J=7 Hz);
1.35 (6H, singlet);
1.43 (3H, singlet);
1.7-2.3 (2H, nd);
1.79 (2H, singlet);
2.27 (3H, singlet);
2.70 (2H, broad triplet, J=6 Hz);
3.07 (1H, doublet of doublets, J=7.5 .delta. 15 Hz);
3.32 (1H, doublet of doublets, J=7.5 .delta. 15 Hz);
3.91 (2H, AB type, J=9 Hz);
4.18 (2H, quartet, J=7 Hz);
4.37 (1H, triplet, J=7 Hz);
6.72 (1H, singlet);
6.85 (1H, singlet);
6.86 (2H, doublet, J=9 Hz);
7.16 (2H, doublet, J=9 Hz).
PREPARATION 24
6-Acetoxy-2-(4-aminophenoxymethyl)-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbut
yl)chroman (Step D2)
12.3 g of
6-acetoxy-2-methyl-2-(4-nitrophenoxymethyl)-7-(1,1,3,3-tetramethylbutyl)ch
roman-4-one (prepared as described in Preparation 19) were
dissolved in a mixture of 200 ml of methanol and 20 ml of benzene,
and then catalytically reduced for 6 hours at room temperature, in
the presence of 2.4 g of 10% w/w palladium-on-carbon, under 1
atmosphere (about 1 bar) pressure of hydrogen. The catalyst was
filtered off, and the filtrate was condensed by evaporation under
reduced pressure. The residue was purified by silica gel column
chromatography, eluted with a 4:1 by volume mixture of benzene and
ethyl acetate, to give the title compound.
Rf value on silica gel thin layer chromatography =0.29 (developing
solvent, benzene:ethyl=4:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.78 (9H, singlet);
1.37 (6H, singlet);
1.52 (3H, singlet);
1.83 (2H, singlet);
2.30 (3H, singlet);
2.66 (1H, doublet, J=17 Hz);
3.10 (1H, doublet, J=17 Hz);
3.4 (2H, broad singlet, disappeared on adding heavy water);
3.92 .delta. 4.06 (2H, AB type, J=9 Hz);
6.58 (2H, doublet, J=9 Hz);
6.76 (2H, doublet, J=9 Hz);
7.00 (1H, singlet);
7.50 (1H, singlet).
PREPARATION 25
Ethyl
3-{4-[6-acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmet
hoxy ]phenyl}-2-chloropropionate (Step D3)
Following the same procedure as described in Preparation 18, 9 g of
6-acetoxy-2-(4-aminophenoxymethyl)-2-methyl-7-(1,1,3,3-tetramethylbutyl)
chroman-4-one (prepared as described in Preparation 24), 1.8 g of
sodium nitrite, 10 ml of concentrated hydrochloric acid, 20 g of
ethyl acrylate, 0.3 g of cuprous oxide, 100 ml of acetone and about
8 ml of water were reacted, to give the title compound.
Rf value on silica gel thin layer chromatography=0.32 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.78 (9H, singlet);
1.23 (3H, triplet, J=7 Hz);
1.38 (6H, singlet);
1.53 (3H, singlet);
1.85 (2H, singlet);
2.30 (3H, singlet);
2.69 (1H, doublet, J=17 Hz);
3.08 (1H, doublet of doublets, J=7.5 .delta. 15 Hz);
3.10 (1H, doublet, J=17 Hz);
3.32 (1H, doublet of doublets, J=7.5 .delta. 15 Hz);
3.99 .delta. 4.12 (2H, AB type, J=10.5 Hz);
4.18 (2H, quartet, J=7 Hz);
4.36 (1H, triplet, J>7 Hz);
6.82 (2H, doublet, J=9 Hz);
7.01 (1H, singlet);
7.16 (2H, doublet, J=9 Hz);
7.52 (1H, singlet).
PREPARATION 26
5-{4-[6-Acetoxy-2-methyl-4-oxo-7-(1,1,3,3-tetramethylbutyl)chroman-2-ylmeth
oxy]benzyl}-2-iminothiazolidin-4-one
After completing the silica gel column chromatography described in
Example 6, the column was further eluted with a 4:1 by volume
mixture of benzene and tetrahydrofuran, to give the title compound
melting at 125.degree.-130.degree. C.
Nuclear magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO]
.delta.ppm:
0.77 (9H, singlet);
1.39 (6H, singlet);
1.53 (3H, singlet);
1.89 (2H, singlet);
2.34 (3H, singlet);
2.6-3.0 (1H, nd);
2.75 (1H, doublet, J=16 Hz);
3.13 (1H, doublet, J=16 Hz);
3.40 (1H, doublet of doublets, J=4 .delta. 14 Hz);
4.17 (2H, singlet);
4.48 (1H, doublet of doublets, J=4 .delta. 10 Hz);
6.87 (2H, doublet, J=9 Hz);
7.01 (1H, singlet);
7.20 (2H, doublet, J=9 Hz);
7.46 (1H, singlet);
7.8-8.7 (2H, broad, disappeared on adding heavy water.
PREPARATION 27
Ethyl
2-(3,7-dimethyloctyl)-6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1
',3 -dithiane) -2-carboxylate (Step E4)
17.7 ml of a hexane solution containing 1.62 mmole/ml of
butyllithium were added dropwise under a nitrogen stream at a
temperature between -60.degree. C. and -50.degree. C. to a solution
of 2.9 g of diisopropylamine in 30 ml of tetrahydrofuran, and the
mixture was allowed to stand for 10 minutes at room temperature. 10
ml of tetrahydrofuran containing 6 g of ethyl
6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1',3'-dithiane)-2-carbo
xylate (prepared as described in Preparation 3) were added dropwise
to the reaction mixture at -60.degree. C. The reaction mixture was
stirred for 1 hour, and then 5 ml of tetrahydrofuran containing 6.4
g of 3,7-dimethyloctyl bromide were added dropwise, and the mixture
was stirred for a further 1 hour at the same temperature. After the
mixture had been stirred for a further 1 hour at room temperature
and then stirred for 1.5 hours at 45.degree.-50.degree. C., the
resulting mixture was allowed to stand overnight at room
temperature. The reaction mixture was then poured into ice-water
and extracted with ethyl acetate. The extract was washed with a
saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate. The solvent was removed by distillation
under reduced pressure. The residue was purified by silica gel
column chromatography, eluted with a 10:1 by volume mixture of
hexane and ethyl acetate, to give the title compound as a pale
yellow oily substance.
Rf value on silica gel thin layer chromatography=0.57 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.87 (9H, doublet, J=7 Hz);
1.0-2.3 (14H, multiplet);
1.17 (3H, triplet, J=7 Hz);
2.17 (3H, singlet);
2.21 (3H, singlet);
2.3-2.9 (2H, nd);
2.62 (1H, doublet, J=14 Hz);
2.83 (3H, singlet);
2.97-3.5 (2H, multiplet);
3.59 (3H, singlet);
3.73 (1H, doublet, J=14 Hz);
4.03 (1H, quarter, J=7 Hz);
4.07 (1H, quartet, J=7 Hz);
4.88 (2H, singlet).
PREPARATION 28
2-(3,7-Dimethyloctyl)-2-hydroxymethyl-6-methoxymethoxy-5,7,8-trimethylchrom
anspiro-4,2'-(1',3'-dithiane) (Step E5)
20 ml of tetrahydrofuran containing 4 g of ethyl
2-(3,7-dimethyloctyl)-6-methoxymethoxy-5,7,8-trimethylchromanspiro-4,2'-(1
'3'-dithiane)-2-carboxylate (prepared as described in Preparation
27) were added dropwise under a nitrogen stream and whilst
ice-cooling to a mixture of 0.41 g of lithium aluminum hydride and
30 ml of tetrahydrofuran, and the mixture was then stirred for 3
hours at room temperature. About 10 ml of ethyl acetate and about
30 ml of 5% w/v aqueous hydrochloric acid were then added, and the
organic layer was separated. The aqueous layer was further
extracted with ethyl acetate. The organic layer and the ethyl
acetate extract were combined and washed with a saturated aqueous
solution of sodium chloride and then dried over anhydrous sodium
sulfate. The solvent was removed by distillation under reduced
pressure to give the title compound as a pale yellow oil.
Rf value on silica gel thin layer chromatography=0.36 (developing
solvent, benzene:ethyl acetate=20.1 by volume).
Nuclear magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm:
0.87 (9H, doublet, J=7 Hz);
1.0-2.0 (12H, multiplet);
3.0-2.5 (2H, nd);
2.08 (3H, singlet);
2.20 (3, singlet);
2.34 (1H, broad singlet, disappeared on adding heavy water);
2.5-3.0 (3H, multiplet);
2.92 (3H, singlet);
3.0-3.6 (4H, multiplet);
3.61 (3H, singlet); 3.76 (1H, doublet of doublets, J=6 & 12
Hz); 4.89 (2H, singlet).
PREPARATION 29
2-(3,7-Dimethyloctyl)-6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxymet
hyl)chromanspiro-4,2'-(1',3'-dithiane) (Step E6)
0.46 g of a 55% w/w suspension of sodium hydride in mineral oil
were added to a mixture of 3.6 g of
2-(3,7-dimethyloctyl)-2-hydroxymethyl-6-methoxymethoxy-5,7,8-trimethylchro
manspiro-4,2'-(1',3'-dithiane) (prepared as described in
Preparation 28) and 30 ml of dimethylformamide under a nitrogen
stream at room temperature, and the resulting mixture was heated at
50.degree. C. for 2 hours. A mixture of 1.66 g of
p-chloronitrobenzene and 3 ml of benzene was added dropwise, and
then the mixture was heated at 50.degree. C. for 2 hours. The
reaction mixture was then poured into water and extracted with
benzene. The extract was washed with water and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure. The residue was purified by silica gel column
chromatography, eluted with a 50:1 by volume mixture of benzene and
ethyl acetate, to give the title compound.
Rf value on silica gel thin layer chromatography=0.55 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 0.87
(9H doublet, J=7 Hz); 1.0-2.3 (14H, multiplet); 2.08 (3H, singlet);
2.21 (3H, singlet); 2.3-3.0 (3H, multiplet); 2.89 (3H, singlet);
3.0-3.6 (3H, multiplet); 3.61 (3H, singlet); 3.99 (1H, doublet, J=9
Hz); 4.45 (1H, doublet, J=9 Hz); 4.89 (2H, singlet); 6.92 (2H,
doublet, J=9 Hz); 8.17 (2H, doublet, J=9 Hz).
PREPARATION 30
2-(3,7-Dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chr
oman-4-one (Steps E7 and A3, Deprotection)
A mixture of 3.4 g of
2-(3,7-dimethyloctyl)-6-methoxymethoxy-5,7,8-trimethyl-2-(4-nitrophenoxyme
thyl)chromanspiro-4,2'-(1',3'-dithiane) (prepared as described in
Preparation 29), 2.2 g of mercuric chloride, 1.7 g of mercuric
oxide, 10 ml of tetrahydrofuran, 27 ml of methanol and 3 ml of
water was heated under reflux for 2 hours. Benzene was then added
to the reaction mixture, and the insoluble residue was filtered
off. The filtrate was washed with an aqueous ammonium sulfate
solution, and then with water, and dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure. 30
ml of benzene, 10 ml of acetic acid and 0.5 ml of 10% w/v aqueous
sulfuric acid was added to the residue, and the mixture was heated
under reflux for 30 minutes. The reaction mixture was then poured
into water and extracted with benzene. The extract was washed with
water and dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure. The residue was subjected to
silica gel column chromatography, eluted with a 100:3 by volume
mixture of benzene and ethyl acetate, and the resulting crystals
were recrystallized from a mixture of benzene and hexane to give
the title compound, melting at 121.degree.-123.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 0.85
(9H, doublet, J=7 Hz); 1.0-1.7 (10H, multiplet); 1.7-2.1 (2H,
multiplet); 2.11 (3H, singlet); 2.21 (3H, singlet); 2.55 (3H,
singlet); 2.76 & 2.98 (2H, AB type, J=16 Hz); 4.16 (2H,
singlet); 4.57 (1H, singlet, disappeared on adding heavy water);
7.96 (2H, doublet, J=9 Hz); 8.20 (2H, doublet, J=9 Hz);
PREPARATION 31
6-Acetoxy-
2-(3,7-dimethyloctyl)-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-on
e (Step A3, Acylation)
Following the same procedure as described in Preparation 16, 1.8 g
of
2-(3,7-dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)ch
roman-4-one (prepared as described in Preparation 30), 0.5 g of
acetic anhydride, 5 ml of pyridine and 10 ml of benzene were
reacted, to give the title compound.
Rf value on silica gel thin layer chromatography=0.41 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 0.85
(9H, doublet, J=7 Hz); 1.0-2.0 (12H, multiplet); 2.08 (3H,
singlet); 2.11 (3H, singlet); 2.33 (3H, singlet); 2.41 (3H,
singlet); 2.80 & 3.00 (2H, AB type, J=16 Hz); 4.17 (2H,
singlet); 6.95 (2H, doublet, J=9 Hz); 8.20 (2H, doublet, J=9
Hz).
PREPARATION 32
6-Acetoxy-2-(4-aminophenoxymethyl)-2-(3,7-dimethyloctyl-5,7,8-trimethylchro
man-4-one (Step D2)
Following the same procedure as described in Preparation 24, 1.95 g
of
6-acetoxy-2-(3,7-dimethyloctyl)-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)ch
roman-4-one (prepared as described in Preparation 31) were treated
with 0.4 g of 10% w/w palladium-on-carbon, to give the title
compound.
Rf value on silica gel thin layer chromatography=0.31 (developing
solvent, benzene:ethyl acetate=4:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 0.85
(9H, doublet, J=7 Hz); 1.0-2.0 (12H, multiplet); 2.09 (3H,
singlet); 2.13 (3H, singlet); 2.32 (3H, singlet); 2.41 (3H,
singlet); 2.77 & 3.00 (2H, AB type, J=16 Hz); 3.4 (2H, broad
singlet, disappeared on adding heavy water); 3.99 (2H, singlet);
6.60 (2H, doublet, J=9 Hz); 6.70 (2H, doublet, J=9 Hz).
PREPARATION 33
Ethyl
3-{4-[6-acetoxy-2-(3,7-dimethyloctyl)-5,7,8-trimethyl-4-oxochroman-2-ylmet
hoxy]phenyl}-2-chloropropionate (Step D3)
Following the same procedure as described in Preparation 18, 1.6 g
of
6-acetoxy-2-(4-aminophenoxymethyl)-2-(3,7-dimethyloctyl)-5,7,8-trimethylch
roman-4-one (prepared as described in Preparation 32), 0.28 g of
sodium nitrite, 1.7 ml of concentrated hydrochloric acid, 3.3 ml of
ethyl acrylate and 0.1 g of cuprous oxide were reacted, to give the
title compound.
Rf value on silica gel thin layer chromatography=0.45 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 0.86
(9H, doublet, J=7 Hz); 1.0-2.0 (12H, multiplet); 1.24 (3H, triplet,
J=7 Hz); 2.09 (3H, singlet); 2.13 (3H, singlet); 2.33 (3H,
singlet); 2.42 (3H, singlet); 2.80 & 2.98 (2H, AB type, J=16
Hz); 3.07 (1H, doublet of doublets, J=7 & 14 Hz); 3.31 (1H,
doublet of doublets, J=7 & 14 Hz); 4.06 (2H, singlet); 4.18
(2H, quartet, J=7 Hz); 4.37 (1H, triplet, J=7 Hz); 6.83 (2H,
doublet, J=9 Hz); 7.15 (2H, doublet, J=9 Hz).
PREPARATION 34
6-Methoxymethoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroma
n (Step A2, Introduction of Aromatic group)
0.96 g of a 55% w/w suspension of sodium hydride in mineral oil was
washed 4 times with cyclohexane and then slowly added to a mixture
of 5.0 g of
2-hydroxymethyl-6-methoxymethoxy-2,5,7,8-tetramethylchroman
(prepared as described in Preparation 1 of copending U.S. Ser. No.
644,996) and 20 ml of dimethylformamide, under a nitrogen stream at
room temperature. The reaction mixture was heated at 50.degree. C.
for 10 minutes and then cooled to 10.degree. C. 4.2 g of
2-chloro-5-nitropyridine were then added in limited amounts. The
reaction mixture was allowed to stand overnight at room temperature
and poured into water. The resulting mixture was extracted with
benzene. The extract was washed with water and dried over sodium
sulfate. The solvent was distilled off under reduced pressure, and
the residue was purified by silica gel column chromatography,
eluted with a 25:1 by volume mixture of benzene and ethyl acetate,
to give the title compound.
Rf value on silica gel thin layer chromatography=0.56 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.40
(3H, singlet); 1.7-2.3 (2H, multiplet); 2.02 (3H, singlet); 2.17
(6H, singlet); 2.65 (2H, broad triplet, J=6 Hz); 3.61 (3H,
singlet); 4.51 (2H, singlet); 4.88 (2H, singlet); 6.87 (1H,
doublet, J=9 Hz); 8.37 (1H, doublet of doublets, J=9 & 3 Hz);
9.06 (1H, doublet, J=3 Hz).
PREPARATION 35
6-Hydroxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman
(Step A3, Deprotection)
1 g of 10% w/v aqueous sulfuric acid was added to 45 ml of acetic
acid containing 5.2 g of
6-methoxymethoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chrom
an prepared as described in Preparation 34), and the resulting
mixture was heated at 55.degree.-58.degree. C. for 15 minutes. The
reaction mixture was cooled, poured into a mixture of 75 g of
sodium bicarbonate and 75 g of ice, and then extracted with ethyl
acetate. The extract was washed with water and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure. The residue gave the title compound as a light-brown
oil.
Rf value on silica gel thin layer chromatography=0.46 developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.39
(3H, singlet); 1.7-2.3 (2H, multiplet); 2.05 (3H, singlet); 2.11
(3H, singlet); 2.15 (3H, singlet); 2.67 (2H, broad triplet, J=6
Hz); 4.19 (1H, singlet, disappeared on adding heavy water); 4.50
(2H, singlet), 6.85 (1H, doublet, J=9 Hz); 8.36 (1H, doublet of
doublets, J=9 & 3 Hz); 9.06 (1H, doublet, J=3 Hz).
PREPARATION 36
6-Acetoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman
(Step A3, Acylation)
Following the same procedure as described in Preparation 16, 5.2 g
of
6-hydroxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman
(prepared as described in Preparation 35), 3 ml of acetic
anhydride, 3 ml of pyridine and about 20 ml of benzene were reacted
to give the title compound.
Rf value on silica gel thin layer chromatography=0.52 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.40
(3H, singlet); 1.7-2.3 (2H , multiplet); 2.02 (9H, singlet); 2.32
(3H, singlet); 2.69 (2H, broad triplet, J=6 Hz); 4.52 (2H, AB type,
J=12 Hz); 6.86 (1H, doublet, J=9 Hz); 8.36 (1H, doublet of
doublets, J=9 & 3 Hz); 9.07 (1H, doublet, J=3 Hz).
PREPARATION 37
6-Acetoxy-2-(5-aminopyridin-2-yloxymethyl)-2,5,7,8-tetramethylchroman
(Step A3, Hydrogenation)
6 g of
6-acetoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman
(pre pared as described in Preparation 36) were dissolved in a
mixture of 80 ml of methanol and 15 ml of benzene, and, in the
presence of 1.5 g of 10% w/w palladium-on-carbon, were
catalytically reduced at room temperature for about 20 hours under
about 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst
was filtered off, and the filtrate was condensed by evaporation
under reduced pressure, to give the title compound.
Rf value on silica gel thin layer chromatography=0.04 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.39
(3H, singlet); 1.6-2.4 (2H, multiplet); 1.97 (3H, singlet); 2.01
(3H, singlet); 2.07 (3H, singlet); 2.30 (3H, singlet); 2.64 (2H,
broad triplet, J=6 Hz); 3.9 (2H, broad singlet, disappeared on
adding heavy water); 4.25 (2H, AB type, J=12 Hz); 6.61 (1H,
doublet, J=9 Hz); 7.02 (1H, doublet of doublets, J=9 & 3 Hz);
7.64 (1H, doublet, J=3 Hz).
PREPARATION 38
Ethyl
3-[2-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)pyridin-5-yl]-2-ch
loropropionate (Step A4)
Following the same procedure as described in Preparation 18, 4.5 g
of
6-acetoxy-2-(5-aminopyridin-2-yloxymethyl)-2,5,7,8-tetramethylchroman
(prepared as described in Preparation 37), 1.1 g of sodium nitrite,
5 ml of concentrated hydrochloric acid, 10 g of ethyl acrylate, 175
mg of cuprous oxide, 40 ml of acetone and about 2.5 g of water were
reacted, to give the title compound.
Rf value on silica gel thin layer chromatography=0.45 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.26
(3H, triplet, J=7.5 Hz); 1.40 (3H, singlet); 1.7-2.3 (2H,
multiplet); 1.99 (3H, singlet); 2.02 (3H, singlet); 2.07 (3H,
singlet); 2.31 (3H, singlet); 2.65 (2H, broad triplet, J=6 Hz);
3.07 (1H, doublet of doublets, J=13.5 & 7.5 Hz); 3.30 (1H,
doublet of doublets, J=13.5 & 7.5 Hz); 4.0-4.5 (5H, multiplet);
6.72 (1H, doublet, J=9 Hz); 7.48 (1H, doublet of doublets, J=9
& 3 Hz); 8.02 (1H, doublet, J=3 Hz).
PREPARATION 39
5-Acetoxy-4-t-butyl-2-hydroxyacetophenone
A mixture of 100 g of t-butylhydroquinone, 130 ml of acetic
anhydride and 1 kg of a boron trifluoride-acetic acid complex salt
(boron trifluoride content 40%) was heated for 2 hours at
60.degree. C. whilst stirring, and was then heated for a further 2
hours at 90.degree. C. The reaction mixture was cooled, and then it
was poured into 3 liters of ice-water and extracted with benzene.
The benzene extract was washed with a saturated aqueous solution of
sodium bicarbonate and then with water and dried over anhydrous
sodium sulfate. The solvent was distilled off and the resulting
oily residue was purified by silica gel column chromatography
eluted with benzene, to give the title compound, melting at
86.5.degree.-87.5.degree. C.
PREPARATION 40
6-Acetoxy-7-t-butyl-2-methyl-2-(2-methyl-5-nitrophenoxymethyl)chroman-4-one
(Step D1)
Following the same procedure as described in Preparation 19, 4.78 g
of 5-acetoxy-4-t-butyl-2-hydroxyacetophenone (prepared as described
in Preparation 39), 4.0 g of
1-(2-methyl-5-nitrophenoxy)propan-2-one, 2.0 g of pyrrolidine, 50
ml of benzene, 4 ml of acetic anhydride and 50 ml of pyridine were
reacted, to give the title compound, as a slightly red, foamy
substance.
Rf value on silica gel thin layer chromatography=0.24 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO] .delta.
ppm: 1.32 (9H, singlet); 1.63 (3H, singlet); 2.17 (3H, singlet);
2.32 (3H, singlet); 2.90 (1H, doublet, J=16.5 Hz); 3.15 (1H,
doublet, J=16.5 Hz); 4.43 (2H, AB type, J=12 Hz); 6.97 (1H,
singlet); 7.38 (1H, doublet, J=8 Hz); 7.45 (1H, singlet); 7.70-7.90
(2H, multiplet).
PREPARATION 41
6-Acetoxy-2-(5-amino-2-methylphenoxymethyl)-7-t-butyl-2-methylchroman-4-one
(Step D2)
Following the same procedure as described in Preparation 24,
hydrogenation of 7.3 g of
6-acetoxy-7-t-butyl-2-methyl-2-(2-methyl-5-nitrophenoxymethyl)chroman-4-on
e (prepared as described in Preparation 40) in the presence of 1 g
of 10% w/w palladium-on-carbon and 100 ml of ethanol gave the title
compound as a slightly red, foamy substance.
Rf value on silica gel thin layer chromatography=0.13 (developing
solvent, benzene:ethyl acetate=5:1 by volume).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO] .delta.
ppm: 1.33 (9H, singlet); 1.56 (3H, singlet); 1.95 (3H, singlet);
2.31 (3H, singlet); 2.80 (1H, doublet, J=16.5 Hz); 3.10 (1H,
doublet, J=16.5 Hz); 4.06 (2H, singlet); 3.90-4.70 (2H, broad,
disappeared on adding heavy water); 6.18 (1H, doublet of doublets,
J=8 & 1.5 Hz); 6.28 (1H, doublet, J=1.5 Hz); 6.78 (1H, doublet,
J=8 Hz); 7.00 (1H, singlet); 7.47 (1H, singlet).
PREPARATION 42
Ethyl
3-[3-(6-acetoxy-7-t-butyl-2-methyl-4-oxochroman-2-ylmethoxy)-4-methylpheny
l]-2-chloropropionate (Step D3)
Following the same procedure as described in Preparation 25, 5.53 g
of
6-acetoxy-2-(5-amino-2-methylphenoxymethyl)-7-t-butyl-2-methylchroman-4-on
e (prepared as described in Preparation 41), 1.2 g of sodium
nitrite, 2.4 ml of concentrated hydrochloric acid, 14 ml of ethyl
acrylate, 190 ml of cuprous oxide and 50 ml of acetone were
reacted, to give the title compound as a pale yellow oil.
Rf value on silica gel thin layer chromatography=0.41 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.22
(3H, triplet, J=7.5 Hz); 1.32 (9H, singlet); 1.57 (3H, singlet);
2.10 (3H, singlet); 2.30 (3H, singlet); 2.74 (1H, doublet, J=17
Hz); 2.94-3.25 (1H, nd); 3.08 (1H, doublet, J=17 Hz); 3.33 (1H,
doublet of doublets, J=7 & 14 Hz); 3.99 & 4.11 (2H, AB
type, J=10 Hz); 4.18 (2H, quartet, J=7.5 Hz); 4.40 (1H, triplet,
J=7 Hz); 6.65-6.85 (2H, nd); 6.99 (1H, singlet); 7.07 (1H, doublet,
J=7.5 Hz); 7.50 (1H, singlet).
PREPARATION 43
6-Acetoxy-2-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one
(Step H1)
A solution of 3 g of potassium t-butoxide in 100 ml of
tetrahydrofuran was added dropwise to a solution of 15 g of
3-acetoxy-2,4,5-trimethyl-6-(4-nitrophenoxyacetoxy)acetophenone in
1 liter of tetrahydrofuran, whilst ice-cooling, and the resulting
mixture was stirred at the same temperature for 2.5 hours. The
reaction mixture was then poured into a mixture of ethyl acetate
and an aqueous solution of sodium chloride, and the organic layer
was separated and dried over anhydrous sodium sulfate. The solvent
was distilled off. The residue was purified by silica gel column
chromatography, eluted with a 1:1 by volume mixture of hexane and
ethyl acetate, to give the title compound, melting at
204.degree.-207.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 SO] .delta.
ppm: 2.05 (3H, singlet); 2.11 (3H, singlet); 2.34 (6H, singlet);
2.76 (1H, doublet, J=17 Hz); 3.24 (1H, doublet, J=17 Hz); 4.28
& 4.50 (2H, AB type, J=10 Hz); 7.24 (2H, doublet, J=9 Hz); 7.30
(1H, singlet, disappeared on adding heavy water); 8.24 (2H, J=9
Hz).
PREPARATION 44
6-Acetoxy-2-(4-aminophenoxymethyl)-2-hydroxy-5,7,8-trimethylchroman-4-one
(Step H2)
Following the same procedure as described in Preparation 24, 7 g of
6-acetoxy-2-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one
(prepared as described in Preparation 43) were treated with 5 g of
10% w/w palladium-on-carbon, 100 ml of tetrahydrofuran and 100 ml
of ethanol, to give the title compound.
Rf value on silica gel thin layer chromatography=0.48 (developing
solvent, ethyl acetate).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 2.08
(3H, singlet); 2.10 (3H, singlet); 2.32 (3H, singlet); 2.41 (3H,
singlet); 2.78 & 3.03 (2H, AB type, J=16 Hz); 3.4-4.3 (3H,
broad singlet, disappeared on adding heavy water); 3.98 & 4.12
(2H, AB type, J=10 Hz); 6.62 (2H, doublet, J=9 Hz); 6.80 (2H,
doublet, J=9 Hz).
PREPARATION 45
Ethyl
3-[4-(6-acetoxy-2-hydroxy-5,7,8-trimethyl-4-oxochroman-2-ylmethoxy)phenyl]
-2-chloropropionate (Step H3)
Following the same procedure as described in Preparation 18, 3.4 g
of
6-acetoxy-2-(4-aminophenoxymethyl)-2-hydroxy-5,7,8-trimethylchroman-4-one
(prepared as described in Preparation 44), 40 ml of acetone, 5 ml
of 35% w/v aqueous hydrochloric acid, 1.2 g of sodium nitrite, 1.6
ml of water, 13 g of ethyl acrylate and 0.32 g of cuprous oxide
were reacted, to give the title compound.
Rf value on silica gel thin layer chromatography=0.20 (developing
solvent, hexane:ethyl acetate=2:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.24
(3H, triplet, J=7 Hz); 2.09 (6H, singlet); 2.33 (3H, singlet); 2.42
(3H, singlet); 2.5-3.6 (4H, nd); 3.9-4.6 (5H, nd); 6.93 (2H,
doublet, J=9 Hz); 7.20 (2H, doublet, J=9 Hz).
PREPARATION 46
Ethyl
3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)phenyl]-2-chloro-2
-methylpropionate (Step A4)
Following the same procedure as described in Preparation 18, 2 g of
6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman
(prepared as described in Preparation 50), 25 ml of acetone, 3 ml
of 35% w/v aqueous hydrochloric acid, 0.7 g of sodium nitrite, 1 ml
of water, 8 g of ethyl methacrylate and 0.2 g of cuprous oxide were
reacted, to give the title compound.
Rf value on silica gel thin layer chromatography=0.54 (developing
solvent, hexane:ethyl acetate=2:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.29
(3H, triplet, J=7 Hz); 1.43 (3H, singlet); 1.68 (3H, singlet); 1.98
(3H, singlet); 2.03 (3H, singlet); 2.09 (3H, singlet); 2.32 (3H,
singlet); 1.5-2.5 (2H, nd); 2.62 (2H, broad triplet, J=7 Hz); 3.18
& 3.36 (2H, AB type, J=17 Hz); 3.84 & 3.98 (2H, AB type,
J=9 Hz); 4.21 (2H, quartet, J=7 Hz); 6.84 (2H, doublet, J=9 Hz);
7.14 (2H, doublet, J=9 Hz).
PREPARATION 47
6-Acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one
(Step D1)
(a) A mixture of 17.7 g of
5-acetoxy-2-hydroxy-3,4,6-trimethylacetophenone, 14.6 g of
4-nitrophenoxyacetone, 7.5 g of pyrrolidine and 60 ml of benzene
was allowed to stand for 1 day at room temperature, and then heated
under reflux for 7 hours using a water separator. Water and ethyl
acetate were added to the reaction mixture. The organic layer was
separated and dried over anhydrous sodium sulfate. The solvent was
distilled off and the resulting residue was purified by silica gel
column chromatography using a 2:1 by volume mixture of hexane and
ethyl acetate as eluent, to give the title compound.
Rf value on silica gel thin layer chromatography=0.17 (developing
solvent, hexane:ethyl acetate=3:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.56
(3H, singlet); 2.10 (6H, singlet); 2.36 (3H, singlet); 2.43 (3H,
singlet); 2.70 (1H, doublet, J=15 Hz); 3.06 (1H, doublet, J=15 Hz);
4.11 (1H, doublet, J=10 Hz); 4.24 (1H, doublet, J=10 Hz); 6.98 (2H,
doublet, J=9 Hz); 8.20 (2H, doublet, J=9 Hz).
(b) A mixture of the same components as mentioned in (a), but
containing piperidine instead of pyrrolidine, was heated under
reflux for 3 hours using a water separator. 5% w/v aqueous
hydrochloric acid was added, and the reaction mixture was extracted
with benzene. The benzene extract was washed with water and dried
over anhydrous sodium sulfate. The solvent was distilled off to
give the title compound. The Rf value and nuclear magnetic
resonance spectrum of this compound accorded with those of the
compound obtained in (a).
(c) In a similar manner to (b), the use of morpholine instead of
piperidine afforded the title compound. The Rf value and nuclear
magnetic resonance spectrum of this compound accorded with those of
the compound obtained in (a).
(d) A mixture of the same components as mentioned in (a), but
containing morpholine instead of pyrrolidine, and toluene instead
of benzene, was heated under reflux for 1 hour. Then, in a similar
manner to (b), the title compound was obtained. The Rf value and
nuclear magnetic resonance spectrum of this compound accorded with
those of the compound obtained in (a).
PREPARATION 48
6-Acetoxy-4-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman
(Step F1)
160 mg of sodium borohydride were added to a mixture of 1.8 g of
6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one
(prepared as described in Preparation 47), 15 ml of methanol and 1
ml of benzene in an ice bath, and the mixture was stirred for 30
minutes. The reaction mixture was then poured into ice-water,
neutralized with 10% w/v aqueous hydrochloric acid and extracted
with benzene. The benzene extract was washed with water and dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure. The residue was purified by silica gel column
chromatography eluted with a 9:1 by volume mixture of benzene and
ethyl acetate, to give crystals. These crystals were recrystallized
from a mixture of benzene and hexane to give the title compound,
melting at 139.degree.-141.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.56
(3H, singlet); 2.05 (6H, singlet); 2.0-2.4 (2H, nd); 2.19 (3H,
singlet); 2.33 (3H, singlet); 4.10 (2H, AB type, J=9 Hz); 5.0 (1H,
doublet of doublets, J=3 & 9 Hz); 7.03 (2H, doublet, J=9 Hz);
8.23 (2H, doublet, J=9 Hz).
PREPARATION 49
6-Acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)-2H-chromene
(Step F3)
Following the procedure described in Preparation 57, 160 mg of
6-acetoxy-4-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman
(prepared as described in Preparation 48), 10 mg of
p-toluenesulfonic acid and 2 ml of benzene gave the title
compound.
Rf value on silica gel thin layer chromatography=0.49 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.59
(3H, singlet); 2.03 (3H, singlet); 2.05 (3H, singlet); 2.09 (3H,
singlet); 2.33 (3H, singlet); 4.10 (2H, AB type, J=9 Hz); 5.73 (1H,
doublet, J=10 Hz); 6.73 (1H, doublet, J=10 Hz); 6.96 (2H, doublet,
J=9 Hz); 8.22 (2H, doublet, J=9 Hz).
PREPARATION 50
6-Acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman (Step
F5)
Following the procedure described in Preparation 58, 100 mg of
6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)-2H-chromene
(prepared as described in Preparation 49) were dissolved in 2 ml of
methanol and, in the presence of 20 mg of 10% w/w
palladium-on-carbon, the compound was reduced under 1 atmosphere
(about 1 bar) pressure of hydrogen, to give the title compound
melting at 138.degree.-140.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.42
(3H, singlet); 2.00 (3H, singlet); about 2 (2H, multiplet); 2.04
(3H, singlet); 2.10 (3H, singlet); 2.31 (3H, singlet); 2.6 (2H,
broad triplet, J=6 Hz); 3.37 (2H, broad, disappeared on adding
heavy water); 3.80 & 3.95 (2H, AB type, J=9 Hz); 6.62 (2H,
doublet, J=7.5 Hz); 6.78 (2H, doublet, J=7.5 Hz).
PREPARATION 51
Ethyl
3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropro
pionate (Step A4)
17.5 g of
6-acetoxy-2-(4-aminophenoxymethyl)-2,5,7,8-tetramethylchroman
(prepared as described in Preparation 50) were dissolved in a
mixture of 130 ml of acetone and 30 ml of water. 13 ml of
concentrated hydrochloric acid, and then 8.5 ml of water containing
4.3 g of sodium nitrite, was added dropwise to this solution in an
ice bath. A further 37.3 ml of ethyl acrylate were then added
dropwise, and then the reaction mixture was heated to
40.degree.-43.degree. C.; at this temperature, 680 mg of cuprous
oxide were added slowly. After about 30 minutes, nitrogen
generation finished. The reaction mixture, which had separated into
two layers, was mixed with benzene to extract the organic layer.
The benzene extract was washed with a saturated aqueous solution of
sodium chloride and then dried over anhydrous sodium sulfate. The
solvent was distilled off and the resulting dark brown oil was
subjected to silica gel column chromatography. After the first
elution with a 1:1 by volume mixture of benzene and cyclohexane,
the title compound was obtained from the next elution with a 2:1 by
volume mixture of benzene and cyclohexane and from the subsequent
elution with benzene alone.
Rf value on silica gel thin layer chromatography=0.39 (developing
solvent, benzene:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.23
(3H, triplet, J=7.5 Hz); 1.42 (3H, singlet); about 2 (2H,
multiplet); 1.98 (3H, singlet); 2.04 (3H, singlet); 2.09 (3H,
singlet); 2.31 (3H, singlet); 2.6 (2H, broad triplet, J=6 Hz); 3.05
(1H, doublet of doublets, J=15 & 7.5 Hz); 3.31 (1H, doublet of
doublets, J=15 & 7.5 Hz); 3.83 & 3.99 (2H, AB type, J=9
Hz); 4.18 (2H, quartet, J=7.5 Hz); 4.38 (1H, triplet, J=7.5 Hz);
6.85 (2H, doublet, J=9 Hz); 7.14 (2H, doublet, J=9 Hz).
PREPARATION 52
6-Hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one
(Step D1)
A mixture of 3.9 g of 2,5 -dihydroxy-3,4,6-trimethylacetophenone,
3.9 g of 4-nitrophenoxyacetone, 2.0 g of pyrrolidine and 15 g of
toluene was allowed to stand for 2 days at room temperature. Dilute
hydrochloric acid was then added to the reaction mixture and the
mixture was extracted with diethyl ether. The aqueous layer was
further extracted with ethyl acetate. The ethyl acetate extract and
the ethereal extract were combined and dried over anhydrous sodium
sulfate. The solvent was distilled off and hexane was added to the
resulting residue. The crystals which separated were collected by
filtration and purified by silica gel column chromatography using a
5:1 by volume mixture of hexane and ethyl acetate as eluent.
Recrystallization of the product from ethyl acetate gave the title
compound, melting at 199.degree.-204.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 SO] .delta.
ppm: 1.43 (3H, singlet); 2.01 (3H, singlet); 2.14 (3H, singlet);
2.46 (3H, singlet); 2.67 (1H, doublet, J=16 Hz); 3.03 (1H, doublet,
J=16 Hz); 4.31 (2H, singlet); 7.19 (2H, doublet, J=9 Hz); 7.92 (1H,
singlet); 8.21 (2H, doublet, J=9 Hz).
PREPARATION 53
7-t-Butyl-6-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one
(Step D1)
Following the procedure described in Preparation 52, the title
compound was prepared from 2.0 g of
4-t-butyl-2,5-dihydroxyacetophenone, 1.9 g of
4-nitrophenoxyacetone, 1.0 g of pyrrolidine and 10 ml of benzene.
The compound obtained melted at 205.degree.-209.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO] .delta.
ppm: 1.39 (3H, singlet); 1.53 (9H, singlet); 2.70 (1H, doublet,
J=16.5 Hz); 3.05 (1H, doublet, J=16.5 Hz); 4.37 (2H, singlet); 6.80
(1H, singlet); 7.18 (2H, doublet, J=10 Hz); 7.22 (1H, singlet);
8.22 (2H, doublet, J=10 Hz); 8.31 (1H, singlet, disappeared on
adding heavy water).
PREPARATION 54
6-Acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one
A mixture of 1.7 g of
7-t-butyl-6-hydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one
(prepared as described in Preparation 53), 1 ml of acetic anhydride
and 10 ml of pyridine was allowed to stand for 1 day at room
temperature. The reaction mixture was then poured into ice-water,
stirred for 2 hours and extracted with benzene. The benzene extract
was washed with 3N aqueous hydrochloric acid, water, a saturated
aqueous solution of sodium bicarbonate and water in that order, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure and the resulting residue was
recrystallized from a mixture of benzene and ethyl acetate (about
10:1 by volume) to give the title compound, melting at
82.degree.-84.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO] .delta.
ppm: 1.33 (9H, singlet); 1.57 (3H, singlet); 2.33 (3H, singlet);
2.82 (1H, doublet, J=16.5 Hz); 3.13 (1H, doublet, J=16.5 Hz); 4.42
(2H, singlet); 6.93 (1H, singlet); 7.25 (2H, doublet, J=9 Hz); 7.44
(1H, singlet); 8.22 (2H, doublet, J=9 Hz).
PREPARATION 55
7-t-Butyl-4,6-dihydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman
(Step F1)
A solution of 3.0 g of
6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman-4-one
(prepared as described in Preparation 54) in 20 ml of
tetrahydrofuran was dropped into a suspension containing 0.3 g of
sodium borohydride in 10 ml of methanol whilst stirring over an ice
bath. After the whole of the solution had been added, the reaction
mixture was stirred for 2 hours at room temperature. The reaction
mixture was then ice-cooled again, acidified weakly with 10% w/v
aqueous hydrochloric acid and extracted with ethyl acetate. The
ethyl acetate extract was washed with water and dried over
anhydrous sodium sulfate. The solvent was removed by evaporation
under reduced pressure to give crystals. Recrystallization of these
crystals from a mixture of benzene and petroleum ether gave the
title compound, melting at 194.degree.-201.degree. C.
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO] .delta.
ppm: 1.34 (9H, singlet); 1.50 (3H, singlet); 1.88 (1H, doublet of
doublets, J=13.5 & 9 Hz); 2.45 (1H, doublet of doublets, J=13.5
& 6 Hz); 2.78 (1H, singlet, disappeared on adding heavy water);
4.15 (2H, singlet); 4.75 (1H, multiplet); 6.62 (1H, singlet); 6.91
(1H, singlet); 7.15 (2H, doublet, J=9 Hz); 8.20 (2H, doublet, J=9
Hz).
PREPARATION 56
4,6-Diacetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman
(Step F2)
3 ml of acetic anhydride were added to a mixture of 2.0 g of
7-t-butyl-4,6-dihydroxy-2-methyl-2-(4-nitrophenoxymethyl)chroman
(prepared as described in Preparation 55) and 20 ml of pyridine,
and the mixture was heated for 3 hours at 50.degree. C. The
reaction mixture was then dissolved in benzene and washed with 3N
aqueous hydrochloric acid, water, a saturated aqueous solution of
sodium bicarbonate and water in that order, and then dried over
anhydrous sodium sulfate. The solvent was distilled off to give the
title compound as a slightly yellow oil.
Rf value on silica gel thin layer chromatography=0.62 (developing
solvent, benzene:ethyl acetate=5:1 by volume).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO] .delta.
ppm: 1.31 (9H, singlet); 1.55 (3H, singlet); 1.77 (3H, singlet);
2.0-2.3 (1H, nd); 2.27 (3H, singlet); 2.45-2.7 (1H, nd); 4.20 &
4.38 (2H, AB type, J=10 Hz); 5.85-6.10 (1H, multiplet); 6.87 (1H,
singlet); 6.98 (1H, singlet); 7.20 (2H, doublet, J=9 Hz); 8.30 (2H,
doublet, J=9 Hz).
PREPARATION 57
6-Acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2H-chromene
(Step F4)
A mixture of 2.4 g of
4,6-diacetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)chroman
(prepared as described in Preparation 56), 0.1 g of
p-toluenesulfonic acid monohydrate and 50 ml of benzene was heated
under reflux for 1 hour. The reaction solution was cooled, washed
with a saturated aqueous solution of sodium bicarbonate, and then
with water, and dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, to give the title
compound as a yellow oil.
Rf value on silica gel thin layer chromatography=0.58 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO] .delta.
ppm: 1.27 (9H, singlet); 1.54 (3H, singlet); 2.27 (3H, singlet);
4.28 (2H, singlet); 5.79 (1H, doublet, J=10 Hz); 6.52 (1H, doublet,
J=10 Hz); 6.67 (1H, singlet); 6.76 (1H, singlet); 7.13 (2H,
doublet, J=9 Hz); 8.20 (2H, doublet, J=9 Hz).
PREPARATION 58
6-Acetoxy-2-(4-aminophenoxymethyl)-7-t-butyl-2-methylchroman (Step
F5)
2.1 g of
6-acetoxy-7-t-butyl-2-methyl-2-(4-nitrophenoxymethyl)-2H-chromene
(prepared as described in Preparation 57) were dissolved in a
mixture of 20 ml of benzene and 2 ml of acetic acid, and the
compound was reduced for 10 hours at room temperature, in the
presence of 0.1 g of 10% w/w palladium-on-carbon, and under about 1
atmosphere (about 1 bar) pressure of hydrogen. The catalyst was
filtered off, and the reaction mixture was washed with a saturated
aqueous solution of sodium bicarbonate and then with water, after
which it was dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography, eluted with benzene,
to give the title compound as a slightly brown oil.
Rf value on silica gel thin layer chromatography=0.13 (developing
solvent, benzene:ethyl acetate=10:1 by volume).
Nuclear Magnetic Resonance Spectrum [(CD.sub.3).sub.2 CO] .delta.
ppm: 1.30 (9H, singlet); 1.40 (3H, singlet); 1.7-2.2 (2H, nd); 2.27
(3H, singlet); 2.73 (2H, broad triplet, J=7 Hz); 3.89 (2H,
singlet); 3.7-4.5 (2H, broad, disappeared on adding heavy water);
6.50-7.05 (6H, multiplet).
PREPARATION 59
Ethyl
3-[4-(6-acetoxy-7-t-butyl-2-methylchroman-2-ylmethoxy)phenyl)-2-chloroprop
ionate (Step A4)
Following the procedure described in Preparation 51, 1.74 g of
6-acetoxy-2-(4-aminophenoxymethyl)-7-t-butyl-2-methylchroman
(prepared as described in Preparation 58), 380 mg of sodium
nitrite, 0.8 ml of concentrated hydrochloric acid, 4.5 g of ethyl
acrylate, 65 mg of cuprous oxide and 17 ml of acetone were reacted,
to give the title compound as a slightly yellow oil.
Rf value on silica gel thin layer chromatography=0.55 (developing
solvent, benzene:ethyl acetate=5:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.23
(3H, triplet, J=7.5 Hz); 1.31 (9H, singlet); 1.45 (3H, singlet);
1.63-2.20 (2H, multiplet); 2.28 (3H, singlet); 2.72 (2H, broad
triplet, J=7 Hz); 3.08 (1H, doublet of doublets, J=7.5 & 15
Hz); 3.30 (1H, doublet of doublets, J=7.5 & 15 Hz); 3.88 &
3.98 (2H, AB type, J=9 Hz); 4.18 (2H, quartet, J=7.5 Hz); 4.37 (1H,
triplet, J=7.5 Hz); 6.73 (1H, singlet); 6.85 (1H, singlet); 6.88
(2H, doublet, J=9 Hz); 7.15 (2H, doublet, J=9 Hz).
PREPARATION 60
6-t-Butoxycarbonylmethoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chrom
an-4-one
A mixture of 5.6 g of sodium hydroxide, 150 ml of ethanol and 20 ml
of water was added dropwise to a mixture of 25 g of
6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman-4-one
(prepared as described in Preparation 47), 30 ml of
dimethylformamide and 150 ml of ethanol, whilst ice-cooling, and
the reaction mixture was stirred for 3 hours. 18.3 g of t-butyl
bromoacetate were then added. The reaction mixture was stirred for
1 hour at room temperature and then allowed to stand overnight.
After this, the reaction mixture was poured into water, neutralized
with a 10% w/v aqueous hydrogen chloride solution and extracted
with benzene. This extract was washed with water and dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the residue was purified by silica gel column
chromatography eluted with a 20:1 by volume mixture of benzene and
ethyl acetate, to give the title compound.
Rf value on silica gel thin layer chromatography=0.49 (developing
solvent, benzene:ethyl acetate=10:1 by volume)
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.53
(12H, singlet); 2.07 (3H, singlet); 2.27 (3H, singlet); 2.57 (3H,
singlet); 2.68 (1H, doublet, J=16.5 Hz); 3.05 (1H, doublet, J=16.5
Hz); 4.17 (2H, singlet, and 2H, AB-type, J=10 Hz); 6.97 (2H,
doublet, J=9 Hz); 8.19 (2H, doublet, J=9 Hz).
PREPARATION 61
6-Ethoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman
1.6 g of a 55% w/w suspension of sodium hydride in mineral oil was
added to a mixture of 11 g of
6-hydroxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman and
100 ml of dimethylformamide, and the reaction mixture was stirred
for 1 hour at room temperature. Then a mixture of 5.7 g of ethyl
iodide and 5 ml of benzene was added dropwise, whilst ice-cooling,
and the reaction mixture was stirred for 2 hours at room
temperature. The reaction mixture was then poured into water and
extracted with benzene. This extract was washed with water and
dried over anhydrous sodium sulfate. The solvent was distilled from
the extract under reduced pressure, and the residue was purified by
silica gel column chromatography eluted with a 3:7 by volume
mixture of cyclohexane and benzene, to give the title compound.
Rf value on silica gel thin layer chromatography=0.48 (developing
solvent, benzene).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.39
(3H, triplet, J=7 Hz); 1.43 (3H, singlet); 1.7-2.1 (2H, nd); 2.06
(3H, singlet); 2.14 (3H, singlet); 2.17 (3H, singlet); 2.63 (2H,
broad triplet, J=7 Hz); 3.72 (2H, quartet, J=7 Hz); 4.00 & 4.08
(2H, AB-type, J=10 Hz); 6.98 (2H, doublet, J=9 Hz); 8.17 (2H,
doublet, J=9 Hz).
PREPARATION 62
2-(4-Aminophenoxymethyl)-6-t-butoxycarboxymethoxy-2,5,7,8-tetramethylchroma
n-4-one
A mixture of 17 g of
6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chro
man-4-one (prepared as described in Preparation 60), 3.5 g of 10%
w/w palladium-on-carbon, 150 ml of methanol and 50 ml of
dimethylformamide was subjected to reduction with Paar's
hydrogenation apparatus under a hydrogen pressure of 3-5
atmospheres (about 3-5 bars) for 7 hours. The palladium-on-carbon
was then filtered off, and the solvent was distilled from the
filtrate under reduced pressure. The residue was dissolved in
benzene, washed with water and dried over anhydrous sodium sulfate.
This solvent was then distilled off under reduced pressure to give
the title compound.
Rf value on silica gel thin layer chromatography=0.29 (developing
solvent, benzene:ethyl acetate=4:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.47
(3H, singlet); 1.54 (9H, singlet); 2.11 (3H, singlet); 2.26 (3H,
singlet); 2.55-2.75 (1H, nd); 2.57 (3H, singlet); 3.05 (1H,
doublet, J=16 Hz); 3.15-3.65 (2H, broad singlet); 3.90 & 4.03
(2H, AB-type, J=10 Hz); 4.17 (2H, singlet); 6.60 (2H, doublet, J=9
Hz); 6.76 (2H, doublet J=9 Hz).
PREPARATION 63
2-(4-Aminophenoxymethyl)-6-ethoxy-2,5,7,8-tetramethylchroman
The procedure described in Preparation 62 was repeated, except that
11 g of
6-ethoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)chroman
(prepared as described in Preparation 61), 2.2 g of 10% w/w
palladium-on-carbon, 100 ml of methanol and 30 ml of benzene were
used as the starting materials to give the title compound, melting
at 121.degree.-123.degree. C.
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.38
(3H, triplet, J=7 Hz); 1.40 (3H, singlet); 1.7-2.1 (2H, nd); 2.08
(3H, singlet); 2.12 (3H, singlet); 2.17 (3H, singlet); 2.60 (2H,
broad triplet, J=7 Hz); 3.1-3.6 (2H, broad, disappeared on adding
heavy water); 3.71 (2H, quartet, J=7 Hz); 3.80 & 3.91 (2H,
AB-type J=10 Hz); 6.60 (2H, doublet, J=9 Hz); 6.78 (2H, doublet,
J=9 Hz).
PREPARATION 64
Ethyl
3-[4-(6-t-Butoxycarbonylmethoxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmetho
xy)phenyl]-2-chloropropionate
16 ml of concentrated hydrochloric acid, 7 ml of an aqueous
solution containing 3.1 g of sodium nitrite and 37 ml of ethyl
acrylate were added, in that order, at 5.degree.-10.degree. C. to a
mixture of 16 g of
2-(4-aminophenoxymethyl)-6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchro
man-4-one (prepared as described in Preparation 62) and 160 ml of
acetone. Then 0.5 g of cuprous oxide was added gradually at an
internal temperature of 40.degree.-43.degree. C. After about 30
minutes, the evolution of nitrogen had ceased. The reaction mixture
was then poured into water and extracted with benzene. This extract
was washed with water and dried over anhydrous sodium sulfate. The
solvent was distilled from the extract under reduced pressure, and
the residue was purified by silica gel column chromatography eluted
with a 9:1 by volume mixture of cyclohexane and ethyl acetate, to
give the title compound.
Rf value on silica gel thin layer chromatography=0.33 (developing
solvent, cyclohexane:ethyl acetate=4:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.23
(3H, triplet, J=7,.5 Hz); 1.50 (3H, singlet); 1.53 (9H, singlet);
2.09 (3H, singlet); 2.26 (3H, singlet); 2.5-2.8 (1H, nd); 2.57 (3H,
singlet); 3.05 (1H, doublet, J=16 Hz); 3.07 (1H, nd); 3.32 (1H,
doublet of doublets, J=7 & 14 Hz); 3.98 & 4.09 (2H,
AB-type, J=10 Hz); 4.05-4.35 (2H, nd); 4.18 (2H, singlet); 4.37
(1H, triplet, J=7 Hz); 6.85 (2H, doublet, J=8 Hz); 7.14 (2H,
doublet, J=8 Hz);
PREPARATION 65
Ethyl
2-chloro-3-[4-(6-ethoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]prop
ionate
The procedure described in Preparation 64 was repeated, except that
9.5 g of
2-(4-aminophenoxymethyl)-6-ethoxy-2,5,7,8-tetramethylchroman
(prepared as described in Preparation 63), 10 ml of concentrated
hydrochloric acid, 2.4 g of sodium nitrite, 26.8 g of ethyl
acrylate, 0.4 g of cuprous oxide and 100 ml of acetone were used as
the starting materials, to give the title compound.
Rf value on silica gel thin layer chromatography=0.30 (developing
solvent, cyclohexane:ethyl acetate=20:1 by volume).
Nuclear Magnetic Resonance Spectrum (CDCl.sub.3) .delta. ppm: 1.23
(3H, triplet, J=7 Hz); 1.38 (3H, triplet, J=7 Hz); 1.41 (3H,
singlet); 1.7-2.1 (2H, nd); 2.07 (3H, singlet); 2.13 (3H, singlet);
2.17 (3H, singlet); 2.60 (2H, broad triplet, J=7 Hz); 3.07 (1H,
doublet of doublets, J=4 & 14 Hz); 3.31 (1H, doublet of
doublets, J=4 & 14 Hz); 3.71 (2H, quartet, J=7 Hz); 3.86 &
3.96 (2H, AB-type, J=9 Hz); 4.17 (2H, quarter, J=7 Hz); 4.36 (1H,
triplet, J=7.5 Hz); 6.85 (2H, doublet, J=9 Hz); 7.13 (2H, doublet,
J=9 Hz).
TEST EXAMPLE 1
Toxicity
The test animals used were male mice of the ddY strain. The animals
were employed in groups of 3. The animals of each group were
administered orally with a single test compound in a dose of 300
mg/kg body weight. The compounds employed were those prepared as
described in Examples 3, 4, 5 and 13. The animals were then
observed for one week after administration, during which time they
showed no abnormalities which could be attributed to the test
compounds. All animals were alive at the end of the 1 week
observation period.
In view of the substantial dose administered to each animal, the
zero mortality indicates that the compounds of the invention have a
very low toxicity.
TEST EXAMPLE 2
Effect on Hyperglycemia
The test animals employed were genetically diabetic male mice of
the KK strain, aged about 6 months. The animals were employed in
groups of 3 (test compounds) or 5 (control) for each test.
The test compounds were suspended in a 0.5% w/v aqueous solution of
carboxymethylcellulose. Each test compound was administered at a
dose of 50 mg/kg body weight.
Within a period of about 3-24 hours after administration, blood
samples were taken from the tip of the tail of each mouse, and the
blood glucose level was measured in this sample by the glucose
oxidase method. The minimum glucose level (i.e. maximum decrease)
was taken for each animal.
A control group was treated with similarly, except that the test
compound was omitted.
The maximum decrease in blood glucose levels was calculated for
each test compound as a percentage of the corresponding level of
the control group. The results are shown in Table 29:
TABLE 29 ______________________________________ Cpd. of Blood
glucose Ex. No. level (%) ______________________________________
Control 100 13 61.5 58 67.5 59 53.4
______________________________________
TEST EXAMPLE 3
Effect on Aldose Reductase
Aldose reductase was separated and partially purified from bovine
lenses by the method of Hayman and Kinoshita [J. Biol. Chem., 240,
877 (1965)]. Enzyme activities were photometrically determined by
the method of Varma et al. [Biochem, Pharmac., 25, 2505
(1976)].
The inhibition of aldose reductase activity was determined
employing each test compound in a concentration of
1.times.10.sup.-5 M, and the results are as shown in Table 30.
As a control, the known compound,
5-[4-(1-methylcyclohexylmethoxy)benzyl]thiazolidine-2,4-dione
("Cpd. A") was tested by the same method and the result is also
shown in Table 30:
TABLE 30 ______________________________________ Cpd. of Percent Ex.
No. Inhibition ______________________________________ 13 55.5 58
51.6 59 79.5 Cpd. A 16.2 ______________________________________
* * * * *